For best viewing of the website please use Mozilla Firefox or Google Chrome.
Serving the Society Since 1986
Articles in press have been peer-reviewed and accepted, which are not yet assigned to volumes/issues, but are citable by Digital Object Identifier (DOI).
Development of A Super-Sensitive Diagnostic Method for African Swine Fever Using CRISPR Techniques
Meishen Ren, Hong Mei, Ming Zhou, Zhen F. Fu, Heyou Han, Dingren Bi, Fuhu Peng, Ling Zhao
doi: 10.1007/s12250-020-00323-1
Received: 12 May 2020 Accepted: 20 October 2020 Published: 07 January 2021
Abstract PDF Springerlink ESM
African swine fever (ASF) is an infectious disease caused by African swine fever virus (ASFV) with clinical symptoms of high fever, hemorrhages and high mortality rate, posing a threat to the global swine industry and food security. Quarantine and control of ASFV is crucial for preventing swine industry from ASFV infection. In this study, a recombinase polymerase amplification (RPA)-CRISPR-based nucleic acid detection method was developed for diagnosing ASF. As a highly sensitive method, RPA-CRISPR can detect even a single copy of ASFV plasmid and genomic DNA by determining fluorescence signal induced by collateral cleavage of CRISPR-lwCas13a (previously known as C2c2) through quantitative real-time PCR (qPCR) and has the same or even higher sensitivity than the traditional qPCR method. A lateral flow strip was developed and used in combination with RPA-CRISPR for ASFV detection with the same level of sensitivity of TaqMan qPCR. Likewise, RPA-CRISPR is capable of distinguishing ASFV genomic DNA from viral DNA/RNA of other porcine viruses without any cross-reactivity. This diagnostic method is also available for diagnosing ASFV clinical DNA samples with coincidence rate of 100% for both ASFV positive and negative samples. RPA-CRISPR has great potential for clinical quarantine of ASFV in swine industry and food security.
Genetic Analysis of Human Adenovirus Type 7 Strains Circulating in Different Parts of China
Yali Duan, Changchong Li, Li Deng, Shuhua An, Yun Zhu, Wei Wang, Meng Zhang, Lili Xu, Baoping Xu, Xiangpeng Chen, Zhengde Xie
doi: 10.1007/s12250-020-00334-y
Received: 24 April 2020 Accepted: 10 October 2020 Published: 05 January 2021
Abstract PDF Springerlink ESM
To investigate the molecular epidemiology and genetic variation of human adenovirus type 7 (HAdV-7) in children with acute respiratory infections (ARI) in China. HAdV-7-positive respiratory samples collected from children with ARI in Beijing, Shijiazhuang, Wenzhou and Guangzhou from 2014–2018 were selected for gene amplification and sequence analysis. Fifty-seven HAdV-7 clinical strains with hexon, penton base and fiber gene sequences were obtained. Meanwhile 17 strains were selected randomly from different cities for whole genome sequencing. Phylogenetic and variation analyses were performed based on the obtained sequences, HAdV-7 prototype strain Gomen (AY594255), vaccine strains (AY495969 and AY594256) and representative sequences of strains. The phylogenetic trees constructed based on whole genome sequences, major capsid protein genes (hexon, penton base and fiber) and the early genes (E1, E2, E3 and E4) were not completely consistent. The HAdV-7 strains obtained in this study always clustered with most of the circulating strains worldwide from the 1980s to the present. Compared with the HAdV-7 prototype strain Gomen (AY594255), some amino acid mutations in loop1 and loop2 of hexon and the RGD loop region of the penton base gene were observed. Recombination analysis showed that partial regions of 55 kDa protein and 100 kDa hexon-assembly associated protein genes among all HAdV-7 strains in this study were from HAdV-16 and HAdV-3, respectively. Our study demonstrated the molecular evolution characteristics of HAdV-7 strains circulating in China and provided basic reference data for the prevention, control and vaccine development of HAdV-7.
Foot-and-Mouth Disease Virus Inhibits RIP2 Protein Expression to Promote Viral Replication
Huisheng Liu, Qiao Xue, Zixiang Zhu, Fan Yang, Weijun Cao, Xiangtao Liu, Haixue Zheng
doi: 10.1007/s12250-020-00322-2
Received: 10 July 2020 Accepted: 17 September 2020 Published: 05 January 2021
Abstract PDF Springerlink ESM
Receptors interaction protein 2 (RIP2) is a specific adaptor molecule in the downstream of NOD2. The role of RIP2 during foot-and-mouth disease virus (FMDV) infection remains unknown. Here, our results showed that RIP2 inhibited FMDV replication and played an important role in the activation of IFN-β and NF-кB signal pathways during FMDV infection. FMDV infection triggered RIP2 transcription, while it reduced the expression of RIP2 protein. Detailed analysis showed that FMDV 2B, 2C, 3Cpro, and Lpro proteins were responsible for inducing the reduction of RIP2 protein. 3Cpro and Lpro are viral proteinases that can induce the cleavage or reduction of many host proteins and block host protein synthesis. The carboxyl terminal 105–114 and 135–144 regions of 2B were essential for reduction of RIP2. Our results also showed that the N terminal 1–61 region of 2C were essential for the reduction of RIP2. The 2C-induced reduction of RIP2 was dependent on inducing the reduction of poly(A)-binding protein 1 (PABPC1). The interaction between RIP2 and 2C was observed in the context of viral infection, and the residues 1–61 were required for the interaction. These data clarify novel mechanisms of reduction of RIP2 mediated by FMDV.
Cell Cycle Arrest Protein CDKN2C Is Not an HBV Host Factor
Guiwen Guan, Liwei Zheng, Jingyuan Xi, Xingwen Yang, Xiangmei Chen, Fengmin Lu
doi: 10.1007/s12250-020-00337-9
Received: 27 July 2020 Accepted: 16 November 2020 Published: 05 January 2021
Abstract PDF Springerlink ESM
Hepatitis B virus (HBV) infection remains a major cause of liver diseases worldwide, which affects approximately 250 million people globally (Yuen et al. 2018). Individuals with chronic HBV infection are at high risk of developing liver cirrhosis, and ultimately hepatocellular carcinoma (HCC). HBV is a Hepadnavirus DNA virus, which specifically infects and efficiently replicates in hepatocytes. It has been proposed for decades that HBV replicates preferentially in non-dividing quiescent hepatocytes (Ozer et al. 1996), therefore remarkably influenced by cell growth and proliferation status. In line with this, a recent study by Carla Eller et al. (2020) reported that by utilizing a genome-wide gain-of-function screen, CDKN2C, the inhibitor of cyclin D (CDK4/6), was identified as an HBV host factor favoring viral replication via cell cycle arrest. In their study, cell cycle arrest is essential for generating a prerequisite cellular environment for CDKN2C to enhance HBV replication. Nevertheless, given the fact that the stealth HBV replicates most efficiently in the quiescent hepatocytes in the immune tolerance phase, it remains to be validated whether CDKN2C virtually serves as an HBV host factor.
Phylogenetic Analysis of the Dengue Virus Strains Causing the 2019 Dengue Fever Outbreak in Hainan, China
Jiang Du, Liyuan Zhang, Xiaoyuan Hu, Ruoyan Peng, Gaoyu Wang, Yi Huang, Wenqi Wang, Kunliang Wu, Qiang Wang, Haoxiang Su, Fan Yang, Yun Zhang, Chuanning Tang, Xiuji Cui, Lina Niu, Gang Lu, Meifang Xiao, Yongguo Du, Feifei Yin
doi: 10.1007/s12250-020-00335-x
Received: 16 August 2020 Accepted: 03 December 2020 Published: 05 January 2021
Abstract PDF Springerlink ESM
Dengue virus is an arthropod-borne pathogen that is transmitted to humans primarily by Aedes spp. mosquitos, causing the acute infectious disease, dengue fever (DF). Until 2019, no dengue outbreak had been reported in Hainan Province for over 20 years. However, in early September of 2019, an increasing number of infected cases appeared and the DF outbreak lasted for over one month in Haikou City, Hainan Province. In our study, we collected 97 plasma samples from DF patients at three hospitals, as well as 1585 mosquito larvae samples from puddles in different areas of Haikou. There were 49 (50.5%) plasma samples found to be strongly positive and 9 (9.3%) plasma samples were weakly positive against the NS1 antigen. We discovered DENV both in the patient's plasma samples and mosquito larvae samples, and isolated the virus from C6/36 cells inoculated with the acute phase serum of patients. Phylogenetic analysis revealed that the new strains were the most closely related to the epidemic strain in the southern regions of China, belonging to lineage IV, genotype I, DENV-1. Compared to the seven closest strains from neighboring countries and provinces, a total of 18 amino acid mutations occurred in the coding sequences (CDS) of the new isolated strain, DENV1 HMU-HKU-2. Our data shows that dengue virus is re-emerged in Hainan, and pose new threats for public health. Thus regular molecular epidemiological surveillance is necessary for control and prevention of DENV transmission.
Metagenomic Profiling of Viruses Associated with Rhipicephalus microplus Ticks in Yunnan Province, China
Junming Shi, Shu Shen, Hui Wu, Yunzhi Zhang, Fei Deng
doi: 10.1007/s12250-020-00319-x
Received: 22 August 2020 Accepted: 10 October 2020 Published: 05 January 2021
Abstract PDF Springerlink ESM
Ticks are well known as vectors of many viruses which usually do great harm to human and animal health. Yunnan Province, widely covered by flourishing vegetation and mainly relying on farming husbandry, is abundant with Rhipicephalus microplus ticks. Therefore, it is of great significance to characterize the viral profile present in R. microplus parasitizing on cattle in Yunnan Province. In this study, a total of 7387 R. microplus ticks were collected from cattle and buffalo in the northwest and southeast areas of Yunnan Province from 2015 to 2017. We investigated the virome of R. microplus using next-generation sequencing (NGS) and the prevalence of important identified viruses among tick groups by RT-PCR. It revealed the presence of diverse virus concerning chu-, rhabdo-, phlebo-, flavi- and parvo- viruses in Yunnan. These viruses consist of single-stranded, circular and segmented sense RNAs, showing a greatly diversity in genomic organization. Furthermore, continuous epidemiological survey among ticks reveals broad prevalence of three viruses (Yunnan mivirus 1, Wuhan tick vrius 1 and YN tick-associated phlebovirus 1) and two possible prevalent viruses including a flavivirus-like segmented virus (Jingmen tick virus) and a bovine hokovirus 2 in Yunnan. Serological investigation among cattle indicates that these identified viruses may be infectious to cattle and can elicit corresponding antibody. Our findings on R. microplus-associated viral community will contribute to the prevention of viral disease and tracking the viral evolution. Further analysis is needed to better elucidate the pathogenicity and natural circulation of these viruses.
Herpesviruses and the Type III Interferon System
Yue Yin, Herman W. Favoreel
doi: 10.1007/s12250-020-00330-2
Received: 09 September 2020 Accepted: 27 October 2020 Published: 05 January 2021
Abstract PDF Springerlink
Type Ⅲ interferons (IFNs) represent the most recently discovered group of IFNs. Together with type I IFNs (e.g. IFN-α/β), type Ⅲ IFNs (IFN-λ) are produced as part of the innate immune response to virus infection, and elicit an anti-viral state by inducing expression of interferon stimulated genes (ISGs). It was initially thought that type I IFNs and type Ⅲ IFNs perform largely redundant functions. However, it has become evident that type Ⅲ IFNs particularly play a major role in antiviral protection of mucosal epithelial barriers, thereby serving an important role in the first-line defense against virus infection and invasion at contact areas with the outside world, versus the generally more broad, potent and systemic antiviral effects of type I IFNs. Herpesviruseses are large DNA viruses, which enter their host via mucosal surfaces and establish lifelong, latent infections. Despite the importance of mucosal epithelial cells in the pathogenesis of herpesviruses, our current knowledge on the interaction of herpesviruses with type Ⅲ IFN is limited and largely restricted to studies on the alphaherpesvirus herpes simplex virus (HSV). This review summarizes the current understanding about the role of IFN-λ in the immune response against herpesvirus infections.
Monocyte/Macrophage-Mediated Innate Immunity in HIV-1 Infection: From Early Response to Late Dysregulation and Links to Cardiovascular Diseases Onset
Eman Teer, Danzil E. Joseph, Richard H. Glashoff, M. Faadiel Essop
doi: 10.1007/s12250-020-00332-0
Received: 29 July 2020 Accepted: 26 October 2020 Published: 05 January 2021
Abstract PDF Springerlink
Although monocytes and macrophages are key mediators of the innate immune system, the focus has largely been on the role of the adaptive immune system in the context of human immunodeficiency virus (HIV) infection. Thus more attention and research work regarding the innate immune system—especially the role of monocytes and macrophages during early HIV-1 infection—is required. Blood monocytes and tissue macrophages are both susceptible targets of HIV-1 infection, and the early host response can determine whether the nature of the infection becomes pathogenic or not. For example, monocytes and macrophages can contribute to the HIV reservoir and viral persistence, and influence the initiation/extension of immune activation and chronic inflammation. Here the expansion of monocyte subsets (classical, intermediate and non-classical) provide an increased understanding of the crucial role they play in terms of chronic inflammation and also by increasing the risk of coagulation during HIV-1 infection. This review discusses the role of monocytes and macrophages during HIV-1 pathogenesis, starting from the early response to late dysregulation that occurs as a result of persistent immune activation and chronic inflammation. Such changes are also linked to downstream targets such as increased coagulation and the onset of cardiovascular diseases.
Development of Improved Mumps Vaccine Candidates by Mutating Viral mRNA Cap Methyltransferase Sites in the Large Polymerase Protein
Xiaoqiang Hao, Yilong Wang, Mengying Zhu, Dongming Zhou, Rongxian Liu, Bin Wang, Yao-Wei Huang, Zhengyan Zhao
doi: 10.1007/s12250-020-00326-y
Received: 26 July 2020 Accepted: 20 October 2020 Published: 07 December 2020
Abstract PDF Springerlink ESM
Although a live attenuated vaccine is available for controlling mumps virus (MuV), mumps still outbreaks frequently worldwide. The attenuated MuV vaccine strain S79 is widely used in mumps vaccination in China, but still with many shortcomings, among which the most prominent are the side effects and decreased immunity. Therefore, there is a need to further improve the safety and efficacy of the current MuV vaccine. In the present study, we further attenuated MuV S79 vaccine strain by inhibiting viral mRNA methyltransferase (MTase). We generated a panel of eight recombinant MuVs (rMuVs) carrying mutations in the MTase catalytic site or S-adenosylmethionine (SAM) binding site in the large (L) polymerase protein. These rMuVs are genetically stable and seven rMuVs are more attenuated in replication in cell culture and five rMuVs are more attenuated in replication in lungs of cotton rats compared with the parental vaccine strain S79. Importantly, cotton rats vaccinated with these seven rMuV mutants produced high levels of serum neutralizing antibodies and were completely protected against challenge with a wild-type MuV strain (genotype F). Therefore, our results demonstrate that alteration in the MTase catalytic site or SAM binding site in MuV L protein improves the safety or the immunogenicity of the MuV vaccine and thus mRNA cap MTase may be an effective target for the development of new vaccine candidates for MuV.
Beta- and Novel Delta-Coronaviruses Are Identified from Wild Animals in the Qinghai-Tibetan Plateau, China
Wentao Zhu, Jing Yang, Shan Lu, Ruiting Lan, Dong Jin, Xue-lian Luo, Ji Pu, Shusheng Wu, Jianguo Xu
doi: 10.1007/s12250-020-00325-z
Received: 03 August 2020 Accepted: 27 September 2020 Published: 01 December 2020
Abstract PDF Springerlink
Outbreaks of severe virus infections with the potential to cause global pandemics are increasingly concerning. One type of those commonly emerging and re-emerging pathogens are coronaviruses (SARS-CoV, MERS-CoV and SARS-CoV-2). Wild animals are hosts of different coronaviruses with the potential risk of cross-species transmission. However, little is known about the reservoir and host of coronaviruses in wild animals in Qinghai Province, where has the greatest biodiversity among the world’s high-altitude regions. Here, from the next-generation sequencing data, we obtained a known beta-coronavirus (beta-CoV) genome and a novel delta-coronavirus (delta-CoV) genome from faecal samples of 29 marmots, 50 rats and 25 birds in Yushu Tibetan Autonomous Prefecture, Qinghai Province, China in July 2019. According to the phylogenetic analysis, the beta-CoV shared high nucleotide identity with Coronavirus HKU24. Although the novel delta-CoV (MtCoV) was closely related to Sparrow deltacoronavirus ISU42824, the protein spike of the novel delta-CoV showed highest amino acid identity to Sparrow coronavirus HKU17 (73.1%). Interestingly, our results identified a novel host (Montifringilla taczanowskii) for the novel delta-CoV and the potential cross-species transmission. The most recent common ancestor (tMRCA) of MtCoVs along with other closest members of the species of Coronavirus HKU15 was estimated to be 289 years ago. Thus, this study increases our understanding of the genetic diversity of beta-CoVs and delta-CoVs, and also provides a new perspective of the coronavirus hosts.
Tumor Necrosis Factor α Reduces SNAP29 Dependent Autolysosome Formation to Increase Prion Protein Level and Promote Tumor Cell Migration
Huan Li, Ren Wang, Ze Yu, Run Shi, Jie Zhang, Shanshan Gao, Ming Shao, Shuzhong Cui, Zhenxing Gao, Jiang Xu, Man-Sun Sy, Chaoyang Li
doi: 10.1007/s12250-020-00320-4
Received: 12 August 2020 Accepted: 10 October 2020 Published: 25 November 2020
Abstract PDF Springerlink ESM
Tumor Necrosis Factor α (TNFα) is best known as a mediator of inflammation and immunity, and also plays important roles in tumor biology. However, the role of TNFα in tumor biology is complex and not completely understood. In a human melanoma cell line, M2, and a lung carcinoma cell line, A549, TNFα up-regulates prion protein (PrP) level, and promotes tumor cell migration in a PrP dependent manner. Silencing PRNP abrogates TNFα induced tumor cell migration; this phenotype is reversed when PRNP is re-introduced. Treatment with TNFα activates nuclear factor kappa B (NF-кB) signaling, which then mitigates autophagy by reducing the expression of Forkhead Box P3 (FOXP3). Down regulation of FOXP3 reduces the transcription of synaptosome associated protein 29 (SNAP29), which is essential in the fusion of autophagosome and lysosome creating autolysosome. FOXP3 being a bona fide transcription factor for SNAP29 is confirmed in a promoter binding assay. Accordingly, silencing SNAP29 in these cell lines also up-regulates PrP, and promotes tumor cell migration without TNFα treatment. But, when SNAP29 or FOXP3 is silenced in these cells, they are no longer respond to TNFα. Thus, a reduction in autophagy is the underlying mechanism by which expression of PrP is up-regulated, and tumor cell migration is enhanced upon TNFα treatment. Disrupting the TNFα-NF-кB-FOXP3-SNAP29 signaling axis may provide a therapeutic approach to mitigate tumor cell migration.
SOX5 Regulates Cell Proliferation, Apoptosis, Migration and Invasion in KSHV-Infected Cells
Wu-Mei Yuan, Ya-Ge Fan, Meng Cui, Ting Luo, Ya-E Wang, Zhan-Jun Shu, Juan Zhao, Jun Zheng, Yan Zeng
doi: 10.1007/s12250-020-00313-3
Received: 01 July 2020 Accepted: 16 September 2020 Published: 24 November 2020
Abstract PDF Springerlink
Kaposi’s sarcoma (KS) originates from vascular endothelial cells, with KS-associated herpesvirus (KSHV) as the etiological agent. SRY-box transcription factor 5 (SOX5) plays different roles in various types of cancer, although its role in KS remains poorly understood. In this study, we identified the role of SOX5 in KS tissues and KSHV-infected cells and elucidated the molecular mechanism. Thirty-two KS patients were enrolled in this study. Measurement of SOX5 mRNA and protein levels in human KS tissues and adjacent control tissues revealed lower levels in KS tissues, with KS patients having higher SOX5 level in the early stages of the disease compared to the later stages. And SOX5 mRNA and protein was also lower in KSHV-infected cells (iSLK-219 and iSLK-BAC) than normal cells (iSLK-Puro). Additionally, SOX5 overexpression inhibited cell proliferation and promoted apoptosis and decreased KSHV-infected cell migration and invasion. Moreover, we found that SOX5 overexpression suppressed the epithelial-to-mesenchymal transition of KSHV-infected cells. These results suggest SOX5 is a suppressor factor during KS development and a potential target for KS treatment.
Generation of A Stable GFP-reporter Zika Virus System for High-throughput Screening of Zika Virus Inhibitors
Jing-Wei Zhang, Han Wang, Jing Liu, Le Ma, Rong-Hong Hua, Zhi-Gao Bu
doi: 10.1007/s12250-020-00316-0
Received: 31 July 2020 Accepted: 18 September 2020 Published: 24 November 2020
Abstract PDF Springerlink ESM
Zika virus (ZIKV) is associated with severe birth defects and Guillain-Barré syndrome and no approved vaccines or specific therapies to combat ZIKV infection are currently available. To accelerate anti-ZIKV therapeutics research, we developed a stable ZIKV GFP-reporter virus system with considerably improved GFP visibility and stability. In this system a BHK-21 cell line expressing DC-SIGNR was established to facilitate the proliferation of GFP-reporter ZIKV. Using this reporter virus system, we established a high-throughput screening assay and screened a selected plant-sourced compounds library for their ability to block ZIKV infection. More than 31 out of 974 tested compounds effectively decreased ZIKV reporter infection. Four selected compounds, homoharringtonine (HHT), bruceine D (BD), dihydroartemisinin (DHA) and digitonin (DGT), were further validated to inhibit wild-type ZIKV infection in cells of BHK-21 and human cell line A549. The FDA-approved chronic myeloid leukemia treatment drug HHT and BD were identified as broad-spectrum flavivirus inhibitors. DHA, another FDA-approved antimalarial drug effectively inhibited ZIKV infection in BHK-21 cells. HHT, BD and DHA inhibited ZIKV infection at a post-entry stage. Digitonin was found to have inhibitory activity in the early stage of viral infection. Our research provides an efficient high-throughput screening assay for ZIKV inhibitors. The active compounds identified in this study represent potential therapies for the treatment of ZIKV infection.
Broad Cell Tropism of SADS-CoV In Vitro Implies Its Potential Cross-Species Infection Risk
Yun Luo, Ying Chen, Rong Geng, Bei Li, Jing Chen, Kai Zhao, Xiao-Shuang Zheng, Wei Zhang, Peng Zhou, Xing-Lou Yang, Zheng-Li Shi
doi: 10.1007/s12250-020-00321-3
Received: 15 July 2020 Accepted: 26 October 2020 Published: 17 November 2020
Abstract PDF Springerlink ESM
Swine acute diarrhoea syndrome coronavirus (SADS-CoV) is a novel swine enteric coronavirus belonged to the Coronaviridae family, Alphacoronavirus genus (Zhou P et al. 2018). The clinical signs of SADS include acute diarrhoea and vomiting, which was similar with the infection of porcine epidemic diarrhea virus (PEDV) and porcine deltacoronavirus (PDCoV) (Wang et al. 2019). The first outbreak of SADS, reported at multiple sites in Guangdong Province, China, led to the death of ten thousands of piglets (Zhou P et al. 2018). Subsequently, retrospective study demonstrated that SADS-CoV had emerged in China since August 2016 (Zhou L et al. 2018). After the devastating outbreak of SADS in January 2017, the re-emergence of SADS-CoV was reported in Fujian and Guangdong provinces in 2018 and 2019, respectively (Li et al. 2018; Zhou et al. 2019).
Sumoylation of Human Parainfluenza Virus Type 3 Phosphoprotein Correlates with A Reduction in Viral Replication
Qi Cheng, Wenjing Huai, Xiaoyan Wu, Mingzhou Chen
doi: 10.1007/s12250-020-00314-2
Received: 11 September 2020 Accepted: 29 September 2020 Published: 16 November 2020
Abstract PDF Springerlink
Human parainfluenza virus type 3 (HPIV3), a member of the Paramyxoviridae family, can cause lower respiratory disease in infants and young children. The phosphoprotein (P) of HPIV3 is an essential cofactor of the viral RNA-dependent RNA polymerase large protein (L). P connects nucleocapsid protein (N) with L to initiate genome transcription and replication. Sumoylation influences many important pathways of the target proteins, and many viral proteins are also themselves sumoylated. In this study, we found that the P of HPIV3 could be sumoylated, and mutation of K492 and K532 to arginine (PK492R/K532R) failed to be sumoylated within P, which enhances HPIV3 minigenome activity. Biochemical studies showed that PK492R/K532R had no effect on its interactions with N, formation of homo-tetramers and formation of inclusion bodies. Finally, we found that incorporation of K492R/K532R into a recombinant HPIV3 (rHPIV3-PK492R/K532R) increased viral production in culture cells, suggesting that sumoylation attenuates functions of P and down-regulates viral replication.
Piperlongumine Inhibits Zika Virus Replication In vitro and Promotes Up-Regulation of HO-1 Expression, Suggesting An Implication of Oxidative Stress
Weizhi Lu, Linjuan Shi, Jing Gao, Huimin Zhu, Ying Hua, Jintai Cai, Xianbo Wu, Chengsong Wan, Wei Zhao, Bao Zhang
doi: 10.1007/s12250-020-00310-6
Received: 16 April 2020 Accepted: 25 August 2020 Published: 13 November 2020
Abstract PDF Springerlink ESM
Owing to the widespread distribution of mosquitoes capable of transmitting Zika virus, lack of clinical vaccines and treatments, and poor immunity of populations to new infectious diseases, Zika virus has become a global public health concern. Recent studies have found that Zika virus can continuously infect human brain microvascular endothelial cells. These cells are the primary components of the blood–brain barrier of the cerebral cortex, and further infection of brain tissue may cause severe damage such as encephalitis and fetal pituitary disease. The present study found that a biologically active base, piperlongumine (PL), inhibited Zika virus replication in human brain microvascular endothelial cells, Vero cells, and human umbilical vein endothelial cells. PL also significantly increased heme oxygenase-1 (HO-1) gene expression, while silencing HO-1 expression and using the reactive oxygen species scavenger, N-acetylcysteine, attenuated the inhibitory effect of PL on Zika virus replication. These results suggest that PL induces oxidative stress in cells by increasing reactive oxygen species. This, in turn, induces an increase in HO-1 expression, thereby inhibiting Zika virus replication. These findings provide novel clues for drug research on the prevention and treatment of Zika virus.
Suppression of HIV-1 Integration by Targeting HIV-1 Integrase for Degradation with A Chimeric Ubiquitin Ligase
Zuopeng Zhang, Sen Yuan, Shuting Xu, Deyin Guo, Lang Chen, Wei Hou, Min Wang
doi: 10.1007/s12250-020-00311-5
Received: 14 March 2020 Accepted: 14 September 2020 Published: 13 November 2020
Abstract PDF Springerlink
Human immunodeficiency virus (HIV) attacks human immune system and causes life-threatening acquired immune deficiency syndrome (AIDS). Treatment with combination antiretroviral therapy (cART) could inhibit virus growth and slow progression of the disease, however, at the same time posing various adverse effects. Host ubiquitin-proteasome pathway (UPP) plays important roles in host immunity against pathogens including viruses by inducing degradation of viral proteins. Previously a series of methods for retargeting substrates for ubiquitin-proteasome degradation have been successfully established. In this study, we attempted to design and construct artificial chimeric ubiquitin ligases (E3s) based on known human E3s in order to manually target HIV-1 integrase for ubiquitin proteasome pathway-mediated degradation. Herein, a series of prototypical chimeric E3s have been designed and constructed, and original substrate-binding domains of these E3s were replaced with host protein domains which interacted with viral proteins. After functional assessment screening, 146LI was identified as a functional chimeric E3 for HIV-1 NL4-3 integrase. 146LI was then further optimized to generate 146LIS (146LI short) which has been shown to induce Lys48-specific polyubiquitination and reduce protein level of HIV-1 NL4-3 integrase more effectively in cells. Lymphocyte cells with 146LIS knock-in generated by CRISPR/Cas-mediated homology-directed repair (HDR) showed remarkably decreased integration of HIV-1 NL4-3 viral DNAs and reduced viral replication without obvious cell cytotoxicity. Our study successfully obtained an artificial chimeric E3 which can induce Lys48-specific polyubiquitination and proteasome-mediated degradation of HIV-1 NL4-3 integrase, thus effectively inhibiting viral DNA integration and viral replication upon virus infection.
A Prognostic Model to Predict Recovery of COVID-19 Patients Based on Longitudinal Laboratory Findings
Suyan Tian, Xuetong Zhu, Xuejuan Sun, Jinmei Wang, Qi Zhou, Chi Wang, Li Chen, Shanji Li, Jiancheng Xu
doi: 10.1007/s12250-020-00317-z
Received: 01 June 2020 Accepted: 09 October 2020 Published: 10 November 2020
Abstract PDF Springerlink
The temporal change patterns of laboratory data may provide insightful clues into the whole course of COVID-19. This study aimed to evaluate longitudinal change patterns of key laboratory tests in patients with COVID-19, and identify independent prognostic factors by examining the associations between laboratory findings and outcomes of patients. This multicenter study included 56 patients with COVID-19 treated in Jilin Province, China, from January 21, 2020 to March 5, 2020. The laboratory findings, epidemiological characteristics and demographic data were extracted from electronic medical records. The average value of eosinophils and carbon dioxide combining power continued to significantly increase, while the average value of cardiac troponin I and mean platelet volume decreased throughout the course of the disease. The average value of lymphocytes approached the lower limit of the reference interval for the first 5 days and then rose slowly thereafter. The average value of thrombocytocrit peaked on day 7 and slowly declined thereafter. The average value of mean corpuscular volume and serum sodium showed an upward trend from day 8 and day 15, respectively. Age, sex, lactate dehydrogenase, platelet count and globulin level were included in the final model to predict the probability of recovery. The above parameters were verified in 24 patients with COVID-19 in another area of Jilin Province. The risk stratification and management of patients with COVID-19 could be improved according to the temporal trajectories of laboratory tests.
Seroprevalence of Neutralizing Antibodies against Six Human Adenovirus Types Indicates the Low Level of Herd Immunity in Young Children from Guangzhou, China
Xingui Tian, Ye Fan, Changbing Wang, Zhenwei Liu, Wenkuan Liu, Yun Xu, Chuncong Mo, Aiping You, Xiao Li, Xia Rong, Rong Zhou
doi: 10.1007/s12250-020-00307-1
Received: 29 June 2020 Accepted: 31 August 2020 Published: 09 November 2020
Abstract PDF Springerlink
Human adenoviruses (HAdVs) commonly cause many diseases such as respiratory diseases, gastroenteritis, cystitis worldwide. HAdV-3, -7, -4 and emergent HAdV-55 and HAdV-14 are the most important types causing severe respiratory diseases. There is no effective drug available for clinical treatment, and no vaccine available for the general population. Therefore, it is important to investigate the seroprevalence against HAdV for developing novel vaccines and vectors. In this study, we investigated the seroprevalence and titer levels of neutralizing antibodies (NAb) against HAdV-3, -4, -7, -14, -55, and -11 in total 278 healthy populations between 0 months and 49 years of age (228 children and 50 adults) from Guangzhou. In children under the age of 18 years, the seropositive rates were significantly increased against HAdV-3 at 12.07%, 33.96%, and 64.29% and against HAdV-7 at 0%, 18.87%, and 19.05% in age groups of 1–2, 3–5, and 6–17 years, respectively. The seroprevalence was very low (0%~8.1%) for all other four types. In adults aged between 18 and 49 years, HAdV-3, -4, and -7 (>50.00%) were the most common types, followed by HAdV-14 (38.00%), -55 (34.00%), and -11 (24.00%). Adults tended to have high NAb titers against HAdV-4 and -55. HAdV-55-seropositive donors tended to be HAdV-11- and HAdV-14-seropositive. These results indicated the low level of herd immunity against all six HAdV types in young children, and HAdV-14, -55, -11 in adults from Guangzhou City. Our findings demonstrate the importance of monitoring HAdV types and developing vaccines against HAdV for children and adults.
Repurposing of Antazoline Hydrochloride as an Inhibitor of Hepatitis B Virus DNA Secretion
Jing Li, Yangyang Hu, Yifei Yuan, Yinan Zhao, Qiqi Han, Canyu Liu, Xue Hu, Yuan Zhou, Yun Wang, Yu Guo, Chunchen Wu, Xinwen Chen, Rongjuan Pei
doi: 10.1007/s12250-020-00306-2
Received: 26 March 2020 Accepted: 16 September 2020 Published: 09 November 2020
Abstract PDF Springerlink
Hepatitis B virus (HBV) belongs to Hepadnaviridae family and mainly infects hepatocytes, which can cause acute or chronic hepatitis. Currently, two types of antiviral drugs are approved for chronic infection clinically: interferons and nucleos(t)ide analogues. However, the clinical cure for chronic infection is still rare, and it is a huge challenge for all researchers to develop high-efficiency, safe, non-tolerant, and low-toxicity anti-HBV drugs. Antazoline hydrochloride is a first-generation antihistamine with anticholinergic properties, and it is commonly used to relieve nasal congestion and in eye drops. Recently, an in vitro high-throughput evaluation system was constructed to screen nearly 800 compounds from the Food and Drug Administration (FDA)-approved Drug Library. We found that arbidol hydrochloride and antazoline hydrochloride can effectively reduce HBV DNA in the extracellular supernatant in a dose-dependent manner, with EC50 of 4.321 μmol/L and 2.910 μmol/L in HepAD38 cells, respectively. Moreover, the antiviral effects and potential mechanism of action of antazoline hydrochloride were studied in different HBV replication systems. The results indicate that antazoline hydrochloride also has a significant inhibitory effect on HBV DNA in the extracellular supernatant of Huh7 cells, with an EC50 of 2.349 μmol/L. These findings provide new ideas for screening and research related to HBV agents.
Loop-Mediated Isothermal Amplification Combined with Lateral Flow Dipstick for On-Site Diagnosis of African Swine Fever Virus
Lei Zuo, Zengxu Song, Yi Zhang, Xiwen Zhai, Yaru Zhai, Xueran Mei, Xin Yang, Hongning Wang
doi: 10.1007/s12250-020-00309-z
Received: 31 July 2020 Accepted: 18 September 2020 Published: 06 November 2020
Abstract PDF Springerlink ESM
African swine fever (ASF) is one of the most important porcine infectious diseases and has caused huge economic losses worldwide (Teklue et al. 2020). African swine fever virus (ASFV), the causative agent of ASF, is a double stranded DNA virus with a genome about 170 to 194 kb in length, and encodes 150 to 167 open reading frames (ORFs). There are more than 50 proteins involved in the mature virions. Among these proteins, p72 encoded by B646L gene is the essential component in the formation of ASFV particles. The sequence of B646L gene is also usually used for the genotyping of ASFV, and there are 24 B646L genotypes (Quembo et al. 2018).
Long-Term Existence of SARS-CoV-2 in COVID-19 Patients: Host Immunity, Viral Virulence, and Transmissibility
Xingyu Wang, Kun Huang, Haini Jiang, Lijuan Hua, Weiwei Yu, Dan Ding, Ke Wang, Xiaopan Li, Zhong Zou, Meilin Jin, Shuyun Xu
doi: 10.1007/s12250-020-00308-0
Received: 13 August 2020 Accepted: 10 September 2020 Published: 06 November 2020
Abstract PDF Springerlink
COVID-19 patients can recover with a median SARS-CoV-2 clearance of 20 days post initial symptoms (PIS). However, we observed some COVID-19 patients with existing SARS-CoV-2 for more than 50 days PIS. This study aimed to investigate the cause of viral clearance delay and the infectivity in these patients. Demographic data and clinical characteristics of 22 long-term COVID-19 patients were collected. The median age of the studied cohort was 59.83 ± 12.94 years. All patients were clinically cured after long-term SARS-CoV-2 infection ranging from 53 to 112 days PIS. Peripheral lymphocytes counts were normal. The ratios of interferon gamma (IFN-γ)-secreting cells to total CD4+ and CD8+ cells were normal as 24.68% ± 9.60% and 66.41% ± 14.87% respectively. However, the number of IFN-γ-secreting NK cells diminished (58.03% ± 11.78%). All patients presented detectable IgG, which positively correlated with mild neutralizing activity (Mean value neutralisation antibodies titers = 157.2, P = 0.05). No SARS-CoV-2 virus was isolated in Vero E6 cells inoculated with nasopharyngeal swab samples from all patients 50 days PIS, and the cytopathic effect was lacking. But one sample was positive for SARS-CoV-2 nucleic acid test in cell supernatants after two passages. Genome sequencing revealed that only three synonymous variants were identified in spike protein coding regions. In conclusion, decreased IFN-γ production by NK cells and low neutralizing antibodies might favor SARS-CoV-2 long-term existence. Further, low viral load and weak viral pathogenicity were observed in COVID-19 patients with long-term SARS-CoV-2 infection.
Comparison of Clinical and Epidemiological Characteristics of Asymptomatic and Symptomatic SARS-CoV-2 Infection in Children
Jiehao Cai, Xiangshi Wang, Jun Zhao, Yanling Ge, Jin Xu, He Tian, Hailing Chang, Aimei Xia, Jiali Wang, Jinqiang Zhang, Zhongqiu Wei, Jingjing Li, Chuning Wang, Jianshe Wang, Qirong Zhu, Xiaowen Zhai, Mei Zeng
doi: 10.1007/s12250-020-00312-4
Received: 19 July 2020 Accepted: 11 October 2020 Published: 04 November 2020
Abstract PDF Springerlink
To understand the epidemiological and clinical features of the symptomatic and asymptomatic pediatric cases of COVID-19, we carried out a prospective study in Shanghai during the period of January 19 to April 30, 2020. A total of 49 children (mean age 11.5 ± 5.12 years) confirmed with SARS-CoV-2 infection were enrolled in the study, including 11 (22.4%) domestic cases and 38 (77.6%) imported cases. Nine (81.8%) local cases and 12 (31.6%) imported cases had a definitive epidemiological exposure. Twenty-eight (57.1%) were symptomatic and 21 (42.9%) were asymptomatic. Neither asymptomatic nor symptomatic cases progressed to severe diseases. The mean duration of viral shedding for SARS-CoV-2 in upper respiratory tract was 14.1 ± 6.4 days in asymptomatic cases and 14.8 ± 8.4 days in symptomatic cases (P > 0.05). Forty-five (91.8%) cases had viral RNA detected in stool. The mean duration of viral shedding in stool was 28.1 ± 13.3 days in asymptomatic cases and 30.8 ± 18.6 days in symptomatic participants (P > 0.05). Children < 7 years shed viral RNA in stool for a longer duration than school-aged children (P < 0.05). Forty-three (87.8%) cases had seropositivity for antibodies against SARS-CoV-2 within 1–3 weeks after confirmation with infection. In conclusion, asymptomatic SARS-CoV-2 infection may be common in children in the community during the COVID-19 pandemic wave. Asymptomatic cases shed viral RNA in a similar pattern as symptomatic cases do. It is of particular concern that asymptomatic individuals are potentially seed transmission of SARS-CoV-2 and pose a challenge to disease control.
African Swine Fever Virus MGF360-12L Inhibits Type I Interferon Production by Blocking the Interaction of Importin α and NF-кB Signaling Pathway
Yisha Zhuo, Zeheng Guo, Tongtong Ba, Cheng Zhang, Lihua He, Cuiping Zeng, Hanchuan Dai
doi: 10.1007/s12250-020-00304-4
Received: 26 February 2020 Accepted: 13 July 2020 Published: 03 November 2020
Abstract PDF Springerlink ESM
African swine fever (ASF) is an infectious transboundary disease of domestic pigs and wild boar and spreading throughout Eurasia. There is no vaccine and treatment available. Complex immune escape strategies of African swine fever virus (ASFV) are crucial factors affecting immune prevention and vaccine development. MGF360 genes have been implicated in the modulation of the IFN-I response. The molecular mechanisms contributing to innate immunity are poorly understood. In this study, we demonstrated that ASFV MGF360-12L (MGF360 families 12L protein) significantly inhibited the mRNA transcription and promoter activity of IFN-β and NF-кB, accompanied by decreases of IRF3, STING, TBK1, ISG54, ISG56 and AP-1 mRNA transcription. Also, MGF360-12L might suppress the nuclear localization of p50 and p65 mediated by classical nuclear localization signal (NLS). Additionally, MGF360-12L could interact with KPNA2, KPNA3, and KPNA4, which interrupted the interaction between p65 and KPNA2, KPNA3, KPNA4. We further found that MGF360-12L could interfere with the NF-кB nuclear translocation by competitively inhibiting the interaction between NF-кB and nuclear transport proteins. These findings suggested that MGF360-12L could inhibit the IFN-I production by blocking the interaction of importin a and NF-кB signaling pathway, which might reveal a novel strategy for ASFV to escape the host innate immune response.
Hantavirus Infection during Pregnancy
Deng-Hui Lu, Hong Jiang, Jian-Qi Lian
doi: 10.1007/s12250-020-00300-8
Received: 25 January 2020 Accepted: 07 August 2020 Published: 19 October 2020
Abstract PDF Springerlink
Hantavirus infection is a global health challenge, causing widespread public concern. In recent years, cases of hantavirus infection in pregnant women have been reported in many countries. The infected pregnant women and their fetuses appear to have more severe clinical symptoms and worse clinical outcomes. Hence, to study the prevalence of hantavirus infection in pregnant women, this study will focus on the epidemiological distribution of the virus, different virus species penetrating the placental barrier, and factors affecting the incidence and clinical outcome of the infection in pregnant women and their fetuses. In addition, this review will also discuss the diagnostic tools and treatments for pregnant patients and provide an overview of the relevant future research.
A Crowned Killer’s Résumé: Genome, Structure, Receptors, and Origin of SARS-CoV-2
Shichuan Wang, Mirko Trilling, Kathrin Sutter, Ulf Dittmer, Mengji Lu, Xin Zheng, Dongliang Yang, Jia Liu
doi: 10.1007/s12250-020-00298-z
Received: 20 July 2020 Accepted: 31 August 2020 Published: 17 October 2020
Abstract PDF Springerlink
The recent emergence and rapid global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pose an unprecedented medical and socioeconomic crisis, and the disease caused by it, Coronavirus disease 2019 (COVID-19), was declared a pandemic by the World Health Organization (WHO) on March 11, 2020. Chinese scientists and physicians rapidly identified the causative pathogen, which turned out to be a novel betacoronavirus with high sequence similarities to bat and pangolin coronaviruses. The scientific community has ignited tremendous efforts to unravel the biological underpinning of SARS-CoV-2, which constitutes the foundation for therapy and vaccine development strategies. Here, we summarize the current state of knowledge on the genome, structure, receptor, and origin of SARS-CoV-2.
Griffithsin with A Broad-Spectrum Antiviral Activity by Binding Glycans in Viral Glycoprotein Exhibits Strong Synergistic Effect in Combination with A Pan-Coronavirus Fusion Inhibitor Targeting SARS-CoV-2 Spike S2 Subunit
Yanxing Cai, Wei Xu, Chenjian Gu, Xia Cai, Di Qu, Lu Lu, Youhua Xie, Shibo Jiang
doi: 10.1007/s12250-020-00305-3
Received: 12 August 2020 Accepted: 10 September 2020 Published: 14 October 2020
Abstract PDF Springerlink
The pandemic of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has posed a significant threat to global public health and economy, thus calling for the rapid development of effective therapeutics and prophylactics. Repurposing existing medicines with clinical safety profiles offers a more rapid hope of combating COVID-19 pandemic than developing a new therapeutic. For example, remdesivir was originally developed to treat Ebola virus infection and its safety to humans has been confirmed in a phase I clinical trial (Grein et al. 2020). Therefore, it immediately went to clinical trials for in vivo efficacy in treatment of COVID-19 patients after its in vitro anti-SARS-CoV-2 activity was verified (Grein et al. 2020).
PTEN Lipid Phosphatase Activity Enhances Dengue Virus Production through Akt/FoxO1/Maf1 Signaling
Bin Liu, Ting-Ting Gao, Xiao-Yu Fu, Zhen-Hao Xu, Hao Ren, Ping Zhao, Zhong-Tian Qi, Zhao-Ling Qin
doi: 10.1007/s12250-020-00291-6
Received: 10 January 2020 Accepted: 31 July 2020 Published: 12 October 2020
Abstract PDF Springerlink ESM
Dengue virus (DENV) is an arthropod-borne viral pathogen and a global health burden. Knowledge of the DENV-host interactions that mediate virus pathogenicity remains limited. Host lipid metabolism is hijacked by DENV for virus replication in which lipid droplets (LDs) play a key role during the virus lifecycle. In this study, we reveal a novel role for phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in LDs-mediated DENV infection. We demonstrate that PTEN expression is downregulated upon DENV infection through post-transcriptional regulation and, in turn, PTEN overexpression enhances DENV replication. PTEN lipid phosphatase activity was found to decrease cellular LDs area and number through Akt/FoxO1/Maf1 signaling, which, together with autophagy, enhanced DENV replication and virus production. We therefore provide mechanistic insight into the interaction between lipid metabolism and the DENV replication cycle.
Inhibitory Activity of Honeysuckle Extracts against Influenza A Virus In Vitro and In Vivo
Mengwei Li, Yuxu Wang, Jing Jin, Jie Dou, Qinglong Guo, Xue Ke, Changlin Zhou, Min Guo
doi: 10.1007/s12250-020-00302-6
Received: 19 July 2019 Accepted: 11 September 2020 Published: 12 October 2020
Abstract PDF Springerlink
Honeysuckle has been used in the treatment of influenza virus infection for thousands of years in China. However, its main active components and the functional mechanisms remain to be elucidated. Here, four honeysuckle extracts, including acids extract, flavonoids extract, total extract and acids-flavonoids mixture, were prepared to clarify the main active antiviral components. The cytopathic effect reduction assay showed that all the four extracts inhibited the replication of influenza viruses H1N1, H3N2 and the oseltamivir-resistant mutant strain H1N1-H275Y. The acids-flavonoids mixture had the strongest inhibitory effects in vitro with EC50 values of 3.8, 4.1, and >20 μg/mL against H1N1, H3N2 and H1N1-H275Y, respectively, showing competitive antiviral activity with oseltamivir and ribavirin. Honeysuckle acids extract also showed the most significant antiviral activity in vivo. Oral administration of the acids extract at a dosage of 600 mg/kg/d effectively alleviated viral pneumonia, maintained body weight and improved the survival rate to 30% of the mice infected with a lethal dose of H1N1. The results of time-of-drug addition experiment and neuraminidase (NA) inhibition assay showed that honeysuckle extracts had a broad-spectrum inhibitory effect against influenza virus NAs. The flavonoid extract showed the strongest inhibitory effect on the NA of influenza virus H7N9 with an IC50 of 24.7 μg/mL. These results suggested that these extracts might exert their antiviral activity by suppressing the release of influenza viruses. Briefly, our findings demonstrate that acids and flavonoids extracts of honeysuckle are the major antiviral active components, and the acids extract has the potential to be developed into an antiviral agent against influenza virus, especially for oseltamivir-resistant viruses.
Application of Human Adenovirus Genotyping by Phylogenetic Analysis in an Outbreak to Identify Nosocomial Infection
Chuanyu Yang, Chunmei Zhu, Yuan Qian, Jie Deng, Baoyuan Zhang, Runan Zhu, Fang Wang, Yu Sun, Dongmei Chen, Qi Guo, Yutong Zhou, Lei Yu, Ling Cao, Linqing Zhao
doi: 10.1007/s12250-020-00299-y
Received: 14 May 2020 Accepted: 05 August 2020 Published: 01 October 2020
Abstract PDF Springerlink ESM
Nosocomial infections are common in pediatric patients and can be fatal in infants and immunocompromised patients. In September 2018, a high positive rate of human adenovirus HAdV was occurred among hospitalized children in the Children's Hospital Affiliated to the Capital Institute of Paediatrics in Beijing. To investigate whether this outbreak of HAdV was related to nosocomial infections or the result of community infections, we collected respiratory specimens from patients with acute respiratory infections in a respiratory ward during June to December 2018, and screened for respiratory viruses. Among 1,840 cases included, 95 (5.2%, 95/1840) were positive for HAdV and 81 were genotyped based on phylogenetic analysis, including seven as HAdV-1 (8.6%), 30 HAdV-3 (37.0%), two HAdV-6 (2.5%), and 42 HAdV-7 (51.9%). More HAdV-positive samples were collected in August (4.7%, 12/255), September (15.0%, 41/274) and October (6.9%, 17/247), with a peak in September 2018. By combining the results of HAdV phylogenetic analysis with clinical data of patients, there were 77 cases (4.2%, 77/1840; 81.1%, 77/95) excluded from nosocomial infections, eight cases representing possible infections transmitted by visitors or attending parents, three cases without sequences that might have been due to infection transmitted by roommates positive for HAdV, one case of a roommate without an HAdV sequence, and six cases that shared highly homologous sequences with those of their roommates, for which nosocomial infections might be considered. In conclusion, genotyping of HAdVs based on phylogenetic analysis combined with clinical information provides a powerful method to distinguish nosocomial infections from community acquired infection, especially when tracing the origins of nosocomial infections.
From Monovalent to Multivalent Vaccines, the Exploration for Potential Preventive Strategies Against Hand, Foot, and Mouth Disease (HFMD)
Xiangchuan He, Miaomiao Zhang, Chen Zhao, Peiyong Zheng, Xiaoyan Zhang, Jianqing Xu
doi: 10.1007/s12250-020-00294-3
Received: 22 April 2020 Accepted: 25 August 2020 Published: 30 September 2020
Abstract PDF Springerlink
Hand, foot, and mouth disease (HFMD) recently emerged as a global public threat. The licensure of inactivated enterovirus A71 (EV-A71) vaccine was the first step in using a vaccine to control HFMD. New challenges arise from changes in the pathogen spectrum while vaccines directed against other common serotypes are in the preclinical stage. The mission of a broad-spectrum prevention strategy clearly favors multivalent vaccines. The development of multivalent vaccines was attempted via the simple combination of potent monovalent vaccines or the construction of chimeric vaccines comprised of epitopes derived from different virus serotypes. The present review summarizes recent advances in HFMD vaccine development and discusses the next steps toward a safe and effective HFMD vaccine that is capable of establishing a cross-protective antibody response.
Different Laboratory Abnormalities in COVID-19 Patients with Hypertension or Diabetes
Xiaojun Wu, Tong Wang, Yilu Zhou, Xiaofan Liu, Hong Zhou, Yang Lu, Weijun Tan, Mingli Yuan, Xuhong Ding, Jinjing Zou, Ruiyun Li, Hailing Liu, Rob M. Ewing, Yi Hu, Hanxiang Nie, Yihua Wang
doi: 10.1007/s12250-020-00296-1
Received: 09 July 2020 Accepted: 31 August 2020 Published: 30 September 2020
Abstract PDF Springerlink
The pandemic of COVID-19, a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; previously known as 2019-nCoV), has placed an enormous burden on health authorities in 213 countries and territories. At the time of writing, over 26 million cases have been recorded across the world, with more than 870 k associated deaths ( World Bank warns COVID-19 pandemic risks dramatic rise in poverty, with the majority of economies expecting to suffer from falling levels of GDP in 2020.
A Highly Attenuated Mumps Virus Strain of Genotype F Generated by Passaging in Vero Cells
Yajing Zhang, Lixia Xie, Benjie Chai, Juncheng Ruan, Yulin Gu, Biao Niu, Yachun Zhang, Zhenfang Fu, Qi An, Dayong Tian
doi: 10.1007/s12250-020-00292-5
Received: 24 February 2020 Accepted: 28 June 2020 Published: 29 September 2020
Abstract PDF Springerlink ESM
Mumps, caused by mumps virus (MuV), is still a serious threat to the health of children and teenagers. In most mumps cases, the clinical symptoms were parotitis, myalgia, malaise, fever and headache. As a neurotropic virus, MuV infection also causes cerebrospinal fluid pleocytosis in one-third of patients and meningitis in 10% of patients. For very few cases, orchitis and oophoritis also can occur (Carbone and Wolinsky 2001).
A Sensitive and High-Throughput Flow Cytometry-Based Assay for Measuring Antibody Neutralization of Human Adenovirus Type 3
Zhenwei Liu, Xingui Tian, Wenkuan Liu, Yuting Xian, Weilue Chen, Rong Zhou
doi: 10.1007/s12250-020-00295-2
Received: 18 January 2020 Accepted: 24 August 2020 Published: 29 September 2020
Abstract PDF Springerlink ESM
The assessment of neutralization activity is an important step in the evaluation of neutralizing antibodies (NAbs). The traditional methods for measuring the antibody neutralization of human adenovirus type 3 (HAdV-3) are the microneu-tralization (MN) assay, which has insufficient sensitivity, and the plaque reduction neutralization test (PRNT), which is not suitable for high-throughput screening. Herein, we describe the development of a flow cytometry-based neutralization (FCN) assay for measuring the neutralization of sera, cell culture supernatants, and chimeric antibodies against HAdV-3 on the basis of a recombinant HAdV-3 (rHAdV-3) construct expressing the enhanced green fluorescent protein (EGFP). For flow cytometry-based assays, the optimal cell confluence was determined as 90%, and the virus was titrated using the assay. The established FCN assay follows the percentage law and an optimal MOI of not less than 5×10-4 was determined by using a purified chimeric antibody. In addition, comparison of the anti-HAdV-3 NAb titers of 72 human serum samples by the MN and FCN assays, showed that both assays correlated strongly with each other. Our FCN assay was an improvement over the MN assay because the observation period was reduced from 3 to 1 days and data analysis could be performed objectively and robotically. Importantly, the newly established FCN assay allows measurement of the neutralization activity of chimeric antibodies expressed in cell culture supernatants. Thus, this sensitive and high-throughput FCN assay is a useful alternative to the MN assay for measuring the antibody neutralization of HAdV-3 and for screening anti-HAdV-3 NAbs in cell culture supernatants.
Identifying the Risk of SARS-CoV-2 Infection and Environmental Monitoring in Airborne Infectious Isolation Rooms (AIIRs)
Zhi-Gang Song, Yan-Mei Chen, Fan Wu, Lin Xu, Bang-Fang Wang, Lei Shi, Xiao Chen, Fa-Hui Dai, Jia-Lei She, Jian-Min Chen, Edward C. Holmes, Tong-Yu Zhu, Yong-Zhen Zhang
doi: 10.1007/s12250-020-00301-7
Received: 28 May 2020 Accepted: 31 August 2020 Published: 28 September 2020
Abstract PDF Springerlink
Healthcare workers (HCWs) are at high risk of occupational exposure to the new pandemic human coronavirus, SARS-CoV-2, and are a source of nosocomial transmission in airborne infectious isolation rooms (AIIRs). Here, we performed comprehensive environmental contamination surveillance to evaluate the risk of viral transmission in AIIRs with 115 rooms in three buildings at the Shanghai Public Health Clinical Center, Shanghai, during the treatment of 334 patients infected with SARS-CoV-2. The results showed that the risk of airborne transmission of SARS-CoV-2 in AIIRs was low (1.62%, 25/1544) due to the directional airflow and strong environmental hygiene procedures. However, we detected viral RNA on the surface of foot-operated openers and bathroom sinks in AIIRs (viral load: 55.00–3154.50 copies/mL). This might be a source of contamination to connecting corridors and object surfaces through the footwear and gloves used by HCWs. The risk of infection was eliminated by the use of disposable footwear covers and the application of more effective environmental and personal hygiene measures. With the help of effective infection control procedures, none of 290 HCWs was infected when working in the AIIRs at this hospital. This study has provided information pertinent for infection control in AIIRs during the treatment of COVID-19 patients.
Early Serum HBsAg Kinetics as Predictor of HBsAg Loss in Patients with HBeAg-Negative Chronic Hepatitis B after Treatment with Pegylated Interferonα-2a
Minghui Li, Lu Zhang, Yao Lu, Qiqi Chen, Huihui Lu, Fangfang Sun, Zhan Zeng, Gang Wan, Linqing Zhao, Yao Xie
doi: 10.1007/s12250-020-00290-7
Received: 19 January 2020 Accepted: 16 July 2020 Published: 25 September 2020
Abstract PDF Springerlink
Hepatitis B surface antigen (HBsAg) loss is an ideal treatment endpoint for patients with chronic hepatitis B (CHB). We investigated the predictive value of on-treatment HBsAg levels for HBsAg loss in hepatitis B e antigen (HBeAg)-negative CHB patients who received 120-week PEG-IFNα-2a treatment. Serum HBV DNA, HBsAg, and anti-HBs levels were assayed at baseline and every 3 months during the treatment. Of 81 patients, 12 achieved HBsAg loss, 20 achieved HBsAg<100 IU/mL, and 49 maintained HBsAg≥100 IU/mL. HBsAg loss rate was only 3.7% at 48 weeks, while it reached to 11.1% and 14.8% after treatment of 96 weeks and 120 weeks. The cutoff HBsAg levels at 12 weeks predicting HBsAg loss at 96 weeks and 120 weeks of treatment were 400 IU/mL and 750 IU/mL, with AUC 0.725 and 0.722, positive predictive value (PPV) 29.41% and 30.56%, and negative predictive value (NPV) 93.75% and 97.78%, respectively. The cutoff HBsAg levels at 24 weeks predicting HBsAg loss at 96 weeks and 120 weeks of treatment were 174 IU/mL and 236 IU/mL respectively, with AUC 0.925 and 0.922, PPV 40.0% and 46.15%, and both NPV 100%. The predictive ability of the cutoff HBsAg levels at 24 weeks was better than that at 12 weeks for HBsAg loss at either 96 or 120 weeks (χ2=3.880, P=0.049 and χ2=4.412, P=0.036). These results indicate that extended therapy is critical to HBsAg loss in HBeAg-negative CHB patients during PEG-IFN treatment, and the HBsAg level at 24 weeks can be used to predict HBsAg loss during tailoring PEG-IFN therapy.
Novel SFTSV Phylogeny Reveals New Reassortment Events and Migration Routes
Xiaoli Wu, Mingyue Li, Yanfang Zhang, Boyun Liang, Junming Shi, Yaohui Fang, Zhengyuan Su, Mengmeng Li, Wenjing Zhang, Ling Xu, Jun Wang, Qiaoli Wu, Shuang Tang, Hualin Wang, Tao Zhang, Cheng Peng, Xin Zheng, Fei Deng, Shu Shen
doi: 10.1007/s12250-020-00289-0
Received: 08 May 2020 Accepted: 13 July 2020 Published: 22 September 2020
Abstract PDF Springerlink ESM
Severe fever with thrombocytopenia syndrome virus (SFTSV), the causative agent of a febrile human disease, was first identified from central and eastern provinces in China, and later in Japan and South Korea. Hubei Province is one of the major SFTS epidemic areas in the central part of China. This study reported the isolation of 11 new SFTSV strains from patients in Hubei Province collected in 2017. Extensive phylogenetic analyses were conducted based on the complete coding sequences of SFTSV segments including the new strains. It was suggested that five different SFTSV genotypes were circulating in Hubei, and 15 reassortment patterns and migration pathways correlated with each genotype were identified, which was more than previously recognized. Hubei Province was more involved in the evolutionary events of SFTSV than that previously thought in which the evolutionary events of SFTSV were reported to be independent from those in other epidemic regions. Further divergence of SFTSV strains was suggested by pairwise comparison of SFTSV sequences from each genotype and sequence identity normalized to representative strain in genotype C1. Subsequently, amino acid variations specific for genotype(s), strain(s), or cluster(s) were inspected, which may be related to differential biological activity of SFTSV strains/genotypes. In conclusion, we analyzed the current status of SFTSV phylogeny in Hubei Province and discussed the possible events correlated to SFTSV evolution. It provided an in-depth insight into SFTSV evolution, raising concerns for the use of proper SFTSV strains in future studies.
Genetic and Molecular Characterization of H9N2 Avian Influenza Viruses Isolated from Live Poultry Markets in Hubei Province, Central China, 2013–2017
Zhibin Hu, Fuhu Peng, Zhenghui Xiong, Wanpo Zhang, Tingting Li, Yuejun Shi, Jun Xie, Xin Jin, Jingjing Huang, Hongde Xiao, Dingren Bi, Nianhua Song, Zili Li
doi: 10.1007/s12250-020-00260-z
Received: 17 January 2020 Accepted: 24 April 2020 Published: 14 September 2020
Abstract PDF Springerlink ESM
H9N2 subtype avian influenza virus (AIV) is an influenza A virus that is widely spread throughout Asia, where it jeopardizes the poultry industry and provides genetic material for emerging human pathogens. To better understand the epidemicity and genetics of H9 subtype AIVs, we conducted active surveillance in live poultry markets (LPMs) in Hubei Province from 2013 to 2017. A total of 4798 samples were collected from apparent healthy poultry and environment. Real-time RT-PCR revealed that the positivity rate of influenza A was 26.6% (1275/4798), of which the H9 subtype accounted for 50.3% (641/1275) of the positive samples. Of the 132 H9N2 viral strains isolated, 48 representative strains were subjected to evolutionary analysis and genotyping. Phylogenetic analysis revealed that all H9N2 viral genes had 91.1%–100% nucleotide homology, clustered with genotype 57, and had high homology with human H9N2 viruses isolated from 2013 to 2017 in China. Using a nucleotide divergence cutoff of 95%, we identified ten distinct H9N2 genotypes that continued to change over time. Molecular analysis demonstrated that six H9N2 isolates had additional potential glycosylation sites at position 218 in the hemagglutinin protein, and all isolates had I155T and Q226L mutations. Moreover, 44 strains had A558V mutations in the PB2 protein and four had E627V mutations, along with H9N2 human infection strains A/Beijing/1/2016 and A/Beijing/1/2017. These results emphasize that the H9N2 influenza virus in Hubei continues to mutate and undergo mammalian adaptation changes, indicating the necessity of strengthening the surveillance of the AIV H9N2 subtype in LPMs.
Molecular Characterization of Human Respiratory Adenoviruses Infection in Xining City, China In 2018
Juan Yu, Shengcang Zhao, Huaxiang Rao
doi: 10.1007/s12250-020-00282-7
Received: 18 March 2020 Accepted: 05 August 2020 Published: 14 September 2020
Abstract PDF Springerlink
Adenoviruses are non-enveloped, double-stranded DNA viruses belonging to the Adenoviridae family. To date, 100 unique genotypes of adenoviruses have been identified, from species A to G, could cause respiratory tract, gastrointestinal tract and ocular infections in human (Akello et al. 2020). Previous studies have reported that specific adenoviral types are often associated with certain clinical symptoms, epidemiological settings and demographic risk groups. Human adenovirus (HAdV) genotypes HAdV-B, HAdV-C, and HAdV-E are usually associated with respiratory infection; HAdV-A, -D, -F, and -G with gastrointestinal disease; and HAdV-D and E with ocular diseases in the healthy individuals (Lynch et al. 2011). Although HAdVs infection is mild and self-limited in the healthy individuals, it can be life-threatening in immune-compromised patients (Echavarria 2008).
Porcine Immunoglobulin Fc Fused P30/P54 Protein of African Swine Fever Virus Displaying on Surface of S. cerevisiae Elicit Strong Antibody Production in Swine
Chen Chen, Deping Hua, Jingxuan Shi, Zheng Tan, Min Zhu, Kun Tan, Lilin Zhang, Jinhai Huang
doi: 10.1007/s12250-020-00278-3
Received: 06 December 2019 Accepted: 13 July 2020 Published: 11 September 2020
Abstract PDF Springerlink ESM
African swine fever virus (ASFV) infects domestic pigs and European wild boars with strong, hemorrhagic and high mortality. The primary cellular targets of ASFV is the porcine macrophages. Up to now, no commercial vaccine or effective treatment available to control the disease. In this study, three recombinant Saccharomyces cerevisiae (S. cerevisiae) strains expressing fused ASFV proteins-porcine Ig heavy chains were constructed and the immunogenicity of the S. cerevisiae-vectored cocktail ASFV feeding vaccine was further evaluated. To be specific, the P30-Fcγ and P54-Fcα fusion proteins displaying on surface of S. cerevisiae cells were produced by fusing the Fc fragment of porcine immunoglobulin IgG1 or IgA1 with p30 or p54 gene of ASFV respectively. The recombinant P30-Fcγ and P54-Fcα fusion proteins expressed by S. cerevisiae were verified by Western blotting, flow cytometry and immunofluorescence assay. Porcine immunoglobulin Fc fragment fused P30/P54 proteins elicited P30/P54-specific antibody production and induced higher mucosal immunity in swine. The absorption and phagocytosis of recombinant S. cerevisiae strains in IPEC-J2 cells or porcine alveolar macrophage (PAM) cells were significantly enhanced, too. Here, we introduce a kind of cheap and safe oral S. cerevisiae-vectored vaccine, which could activate the specific mucosal immunity for controlling ASFV infection.
Seroprevalence of Dengue Virus among Young Adults in Beijing, China, 2019
Ran Wang, Dongying Fan, Lei Wang, Yueqi Li, Hongning Zhou, Na Gao, Jing An
doi: 10.1007/s12250-020-00285-4
Received: 16 May 2020 Accepted: 05 August 2020 Published: 11 September 2020
Abstract PDF Springerlink ESM
Dengue is one of the major mosquito-borne diseases and prevalent across tropical and subtropical regions (Carod-Artal et al. 2013; Ferguson 2018). Infection with four serotypes of dengue virus (DENV1–4) individually or multiply may cause severe clinical manifestations and complications. In the mainland of China, dengue had been usually characterized as an imported epidemic disease in the past. The first confirmed outbreak of dengue caused by DENV4 occurred in 1978 in Guangdong, a province in south China (Sang et al. 2016). Since then, dengue occurred predominantly in south China, and expanded gradually to east and southwest China (Wu et al. 2010). Currently, each serotype of DENV circulates and distributes throughout China (Wu et al. 2010; Lai et al. 2015). Moreover, the retrospective researches suggested that the regions reporting indigenous dengue cases had incessantly traversed its geographic limits from southeast coastal provinces to central or western provinces within China (Sang et al. 2016), due to the change of vectorial capacity of mosquitoes and global climate (Misslin et al. 2016). Thus, the increasing prevalence of dengue has posed a serious threat to public health in China.
Comparative Antiviral Efficacy of Viral Protease Inhibitors against the Novel SARS-CoV-2 In Vitro
Leike Zhang, Jia Liu, Ruiyuan Cao, Mingyue Xu, Yan Wu, Weijuan Shang, Xi Wang, Huanyu Zhang, Xiaming Jiang, Yuan Sun, Hengrui Hu, Yufeng Li, Gang Zou, Min Zhang, Lei Zhao, Wei Li, Xiaojia Guo, Xiaomei Zhuang, Xing-Lou Yang, Zheng-Li Shi, Fei Deng, Zhihong Hu, Gengfu Xiao, Manli Wang, Wu Zhong
doi: 10.1007/s12250-020-00288-1
Received: 04 August 2020 Accepted: 14 August 2020 Published: 10 September 2020
Abstract PDF Springerlink
The recent outbreak of novel coronavirus pneumonia (COVID-19) caused by a new coronavirus has posed a great threat to public health. Identifying safe and effective antivirals is of urgent demand to cure the huge number of patients. Virus-encoded proteases are considered potential drug targets. The human immunodeficiency virus protease inhibitors (lopinavir/ritonavir) has been recommended in the global Solidarity Trial in March launched by World Health Organization. However, there is currently no experimental evidence to support or against its clinical use. We evaluated the antiviral efficacy of lopinavir/ritonavir along with other two viral protease inhibitors in vitro, and discussed the possible inhibitory mechanism in silico. The in vitro to in vivo extrapolation was carried out to assess whether lopinavir/ritonavir could be effective in clinical. Among the four tested compounds, lopinavir showed the best inhibitory effect against the novel coronavirus infection. However, further in vitro to in vivo extrapolation of pharmacokinetics suggested that lopinavir/ritonavir could not reach effective concentration under standard dosing regimen [marketed as Kaletra®, contained lopinavir/ritonavir (200 mg/50 mg) tablets, recommended dosage is 400 mg/10 mg (2 tablets) twice daily]. This research concluded that lopinavir/ritonavir should be stopped for clinical use due to the huge gap between in vitro IC50 and free plasma concentration. Nevertheless, the structure–activity relationship analysis of the four inhibitors provided further information for de novel design of future viral protease inhibitors of SARS-CoV-2.
Characterizing the Lassa Virus Envelope Glycoprotein Membrane Proximal External Region for Its Role in Fusogenicity
Junyuan Cao, Guangshun Zhang, Minmin Zhou, Yang Liu, Gengfu Xiao, Wei Wang
doi: 10.1007/s12250-020-00286-3
Received: 30 April 2020 Accepted: 22 July 2020 Published: 08 September 2020
Abstract PDF Springerlink
The membrane-proximal external region (MPER) of Lassa virus (LASV) glycoprotein complex (GPC) is critical in modulating its functionality. Till now, the high-resolution structure of the intact GPC, including MPER is not available. In this study, we used alanine substitution to scan all 16 residues located in LASV MPER. Western blotting and quantification fusion assay showed that the residues located at the C terminus of the HR2 (M414 and L415) and N terminus of the MPER (K417 and Y419) are critical for GPC-mediated membrane fusion function. Furthermore, cell surface biotinylation experiments revealed that M414A, K417A and Y419A expressed similar levels as WT, whereas L415A mutant led to a reduction of mature GPC on the cell surface. Moreover, substitution of these residues with the similar residue such as M414L, L415I, K417R and Y419F would partly compensate the loss of the fusion activity caused by the alanine mutant in these sites. Results from this study showed that several key residues in the MPER region are indispensable to promote the conformational changes that drive fusion events and shed light on the structure analysis of LASV GPC and anti-LASV therapeutics.
A Study of Two Cases Co-Infected with SARS-CoV-2 and Human Immunodeficiency Virus
Rong Zhang, Xiaohua Chen, Yuqing Huang, Qi Zhang, Yan Cheng, Nan Zhang, Haibo Zhang, Bo Yang, Fang Liu, Yingle Liu, Ke Lan
doi: 10.1007/s12250-020-00280-9
Received: 07 May 2020 Accepted: 13 August 2020 Published: 07 September 2020
Abstract PDF Springerlink
Since December 2019, A new type of coronavirus pneumonia (coronavirus disease 2019, COVID-19) has become endemic in Wuhan, China. So far, COVID-19 has developed into a global epidemic. The body’s immune system plays an important role in the fight against COVID-19. Here, we followed up the clinical data and treatment of two COVID-19 patients diagnosed with acquired immunodeficiency syndrome (AIDS), hoping to be helpful for the subsequent diagnosis and treatment of patients with related diseases.
Termination of Transcription of LAT Increases the Amounts of ICP0 mRNA but Does Not Alter the Course of HSV-1 Infection in Latently Infected Murine Ganglia
Haifang Jiang, Jiaming Wu, Xianjie Liu, Ruitao Lu, Manling Zhou, Meiling Chen, Yonghong Liu, Grace Guoying Zhou, Wenmin Fu
doi: 10.1007/s12250-020-00287-2
Received: 20 May 2020 Accepted: 31 July 2020 Published: 07 September 2020
Abstract PDF Springerlink ESM
On entering sensory ganglia, herpes simplex viruses 1 (HSV-1) establishes a latent infection with the synthesis of a latency associated transcript (LAT) or initiates productive infection with expression of a set of immediate early viral proteins. The precise mechanisms how expression of α genes is suppressed during the latency are unknown. One mechanism that has been proposed is illustrated in the case of ICP0, a key immediate early viral regulatory protein. Specifically, the 2 kb LAT intron is complementary to the 3′ terminal portion of ICP0 mRNA. To test the hypothesis that accumulation of LAT negatively affects the accumulation of ICP0 mRNA, we inserted a DNA fragment encoding two poly(A) sequences into LAT to early terminate LAT transcript without interrupting the complementary sequence of ICP0 transcript (named as SR1603). Comparisons of the parent (SR1601) and mutant (SR1603) HSV-1 viruses showed the following: Neurons harboring latent SR1603 virus accumulated equivalent amounts of viral DNA but higher amounts of ICP0 mRNA and lower amounts of LAT, when compared to neurons harboring the SR1601 virus. One notable difference between the two viruses is that viral RNA accumulation in explanted ganglia harboring SR1603 virus initiated significantly sooner than that in neurons harboring SR1601 virus, suggesting that ICP0 may act as an activator of viral gene expression in permissive cells. Collectively, these data suggest that increased ICP0 mRNA by suppressed LAT did not affect the establishment of latency in latently infected murine ganglia.
Flu Universal Vaccines: New Tricks on an Old Virus
Ruikun Du, Qinghua Cui, Lijun Rong
doi: 10.1007/s12250-020-00283-6
Received: 06 June 2020 Accepted: 05 August 2020 Published: 01 September 2020
Abstract PDF Springerlink
Conventional influenza vaccines are based on predicting the circulating viruses year by year, conferring limited effectiveness since the antigenicity of vaccine strains does not always match the circulating viruses. This necessitates development of universal influenza vaccines that provide broader and lasting protection against pan-influenza viruses. The discovery of the highly conserved immunogens (epitopes) of influenza viruses provides attractive targets for universal vaccine design. Here we review the current understanding with broadly protective immunogens (epitopes) and discuss several important considerations to achieve the goal of universal influenza vaccines.
SARS-CoV-2 Serological Survey of Cats in China before and after the Pandemic
Junhua Deng, Yuxiu Liu, Chunyan Sun, Jingjing Bai, Jie Sun, Liying Hao, Xiangdong Li, Kegong Tian
doi: 10.1007/s12250-020-00284-5
Received: 12 June 2020 Accepted: 03 August 2020 Published: 01 September 2020
Abstract PDF Springerlink
SARS-CoV-2 or COVID-19 has become pandemic and spread to more than 200 countries with over 24 million human infected cases (WHO 2020). The origin of SARS-CoV-2 remains unknown, though bat, pangolin, and snake were reported to be the potential animal reservoirs (Ji et al. 2020; Ward et al. 2020; Chen et al. 2020). Companion animals including dogs and cats were recent sporadically reported to be infected by SARS-CoV-2 with or without clinical symptoms (Li 2020a, b; Sailleau et al. 2020). Recently, both Chinese and American groups reported that cats were highly susceptible to SARS-CoV-2 after artificial inoculation and could spread the virus via respiratory droplets (Shi et al. 2020; Bosco-Lauth et al. 2020). Coincidently, Zhang et al. (2020) reported that 15 of 102 (14.7%) cats in Wuhan City during SARS-CoV-2 outbreak showed serological positive using an in-house indirect enzyme linked immunosorbent assay (ELISA) (Zhang et al. 2020). These reports raise a huge public concern as the infected cats could play a role in transmission of SARS-CoV-2. The high percentage of seropositivity of cats in Wuhan, the epicentre of the SARS-CoV-2 epidemic, could be due to the large number of infected human cases (more than 14 folds than that in other cities) (Table 1) where cats may have been more frequently exposed to SARS-CoV-2 patients or contaminated environment. As yet, SARS-CoV-2 serological prevalence of cats in other Chinese cities remains unknown. Therefore, a serological survey including more cities with numbers of SARS-CoV-2 human cases in China will be valuable for elucidating the role of cats in transmission of the viruses and relieve public concerns. In this study, 630 cat serum samples collected before November 2019 and 423 cat serum samples collected during SARS-CoV-2 outbreak (from February 2020 to April 2020) in 20 cities in China for detecting the prevalence of SARS-CoV-2 specific antibodies.
Coping with COVID-19 in Sub-Saharan Africa: What Might the Future Hold?
Franck J. D. Mennechet, Guy R. Takoudjou Dzomo
doi: 10.1007/s12250-020-00279-2
Received: 04 June 2020 Accepted: 24 July 2020 Published: 01 September 2020
Abstract PDF Springerlink
On December 31st, 2019 an unexplained case of pneumonia was reported in Wuhan, Hubei Province, China (Zhou et al. 2020). On January 9th, 2020, Chinese authorities and the World Health Organization (WHO) officially announced the discovery of a new type of coronavirus called SARS-CoV-2 that causes the coronavirus disease 2019 (COVID-19) (Shereen et al. 2020; WHO 2020j; Zhou et al. 2020). A few months later, the virus is sweeping the world with almost 18 million recorded global cases and 709,000 deaths as of August 7th 2020 (WHO 2020a). After China, Europe and United States, South America is currently the new epicenter of the pandemic, but the situation is worsening in India, and the pandemic is moving fast. Nevertheless, confronted by the disastrous socio-economic consequences of the epidemic, a number of countries have already started a progressive end to the lockdown. Africa confirmed its first case of COVID-19 in Egypt on February 14th. On February 27th, Nigeria reported the first official case of SARS-CoV-2 in the sub-Saharan area, and on March 18th Burkina Faso the first death. On August 7th 2020 this number has risen to more than 1,000,000 cases and caused about 22,000 deaths in Africa according to the Africa Centers for Disease Control and Prevention (Africa CDC) (Africa CDC 2020a). Southern and Northern Africa have currently the highest number of official cases and deaths, but Western Africa is the most impacted by the death toll in sub-Saharan zone, followed by Eastern and Central Africa. However, these numbers are probably undervalued and could represent only the “tip of the iceberg”. According to the WHO, the highest mortality rates for COVID-19 were observed in the Republic of Chad (8.5%), Niger (6.2%), Algeria (5.7%), Angola (5.4%), Burkina Faso (5.3%), Mali (5.1%) and Liberia (4.5%). On July 8th 2020, South Africa, Nigeria, Algeria and Cameroon accounted for 75% of the total official deaths reported in Africa.
Patients with Prolonged Positivity of SARS-CoV-2 RNA Benefit from Convalescent Plasma Therapy: A Retrospective Study
Yongran Wu, Ke Hong, Lianguo Ruan, Xiaobo Yang, Jiancheng Zhang, Jiqian Xu, Shangwen Pan, Lehao Ren, Lu Chen, Chaolin Huang, You Shang
doi: 10.1007/s12250-020-00281-8
Received: 09 July 2020 Accepted: 03 August 2020 Published: 31 August 2020
Abstract PDF Springerlink
Convalescent plasma therapy has been implemented in a few cases of severe coronavirus disease 2019. No report about convalescent plasma therapy in treating patients with prolonged positivity of SARS-CoV-2 RNA has been published. In this study, we conducted a retrospective observational study in 27 patients with prolonged positivity of SARS-CoV-2 RNA, the clinical benefit of convalescent plasma therapy were analyzed. qRT-PCR test of SARS-CoV-2 RNA turned negative (≤ 7 days) in a part of patients (early negative group, n = 15) after therapy, others (late negative group, n = 12) turned negative in more than 7 days. Pulmonary imaging improvement was confirmed in 7 patients in early negative group and 8 in late negative group after CP therapy. Viral load decreased in early negative group compared with late negative group at day 3, 5, 7 after implementing convalescent plasma therapy. Patients in early negative group had a shorter median length of hospital stay. In conclusion, convalescent plasma therapy might help eliminate virus and shorten length of hospital stay in patients with prolonged positivity of SARS-CoV-2 RNA.
Clinical Characteristics of Hospitalized Patients with SARS-CoV-2 and Hepatitis B Virus Co-infection
Xiaoping Chen, Qunqun Jiang, Zhiyong Ma, Jiaxin Ling, Wenjia Hu, Qian Cao, Pingzheng Mo, Lei Yao, Rongrong Yang, Shicheng Gao, Xien Gui, Wei Hou, Yong Xiong, Jinlin Li, Yongxi Zhang
doi: 10.1007/s12250-020-00276-5
Received: 17 May 2020 Accepted: 13 July 2020 Published: 24 August 2020
Abstract PDF Springerlink
Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection was first detected in Wuhan, China in late December 2019. The virus was spreading rapidly to other cities of China and accumulating cases had been reported (Li et al. 2020). On March 11, 2020, WHO declared the outbreak of SARS-CoV-2 as a pandemic. As of June 28, around 10 million COVID-19 cases have been reported in 216 countries or territories and the worldwide death toll has passed 490,000 according to data from WHO ( Until now, there is no effective drug or vaccine available against SARS-Cov-2 infection.
Longitudinal Characteristics of T Cell Responses in Asymptomatic SARS-CoV-2 Infection
Jingyi Yang, Ejuan Zhang, Maohua Zhong, Qingyu Yang, Ke Hong, Ting Shu, Dihan Zhou, Jie Xiang, Jianbo Xia, Xi Zhou, Dingyu Zhang, Chaolin Huang, You Shang, Huimin Yan
doi: 10.1007/s12250-020-00277-4
Received: 28 June 2020 Accepted: 24 July 2020 Published: 21 August 2020
Abstract PDF Springerlink
SARS-CoV-2 causes a spectrum of illness, ranging from an asymptomatic state to life-threatening multi-organ failure, and imposes a high socioeconomic burden on its sufferers and on society (Chen et al. 2020; Pan et al. 2020). Asymptomatic SARS-CoV-2 infection, confirmed by assay with quantitative real-time reverse transcription PCR (qRT-PCR), presented neither clinical symptom nor radiographic abnormality (Pan et al. 2020). While T cell responses are crucial for viral control, viral infection also induces significant count decrease and function impairment of T cells (Chen et al. 2020; Qin et al. 2020). Despite high rate of SARS-CoV-2 asymptomatic infections (Black et al. 2020), T cell responses of this population are still largely unknown. Here, we reported the kinetics of CD4+ and CD8+ T cell responses in an asymptomatic SARS-CoV-2 infected case.
Identification of Aristolactam Derivatives That Act as Inhibitors of Human Immunodeficiency Virus Type 1 Infection and Replication by Targeting Tat-Mediated Viral Transcription
YoungHyun Shin, Chul Min Park, Hong Gi Kim, Dong-Eun Kim, Min Suk Choi, Jeong-ah Kim, Byeong-Sun Choi, Cheol-Hee Yoon
doi: 10.1007/s12250-020-00274-7
Received: 15 May 2020 Accepted: 28 June 2020 Published: 10 August 2020
Abstract PDF Springerlink
Despite the success of antiretroviral therapy (ART), efforts to develop new classes of antiviral agents have been hampered by the emergence of drug resistance. Dibenzo-indole-bearing aristolactams are compounds that have been isolated from various plants species and which show several clinically relevant effects, including anti-inflammatory, antiplatelet, and anti-mycobacterial actions. However, the effect of these compounds on human immunodeficiency virus type 1 (HIV-1) infection has not yet been studied. In this study, we discovered an aristolactam derivative bearing dibenzo[cd,f]indol-4(5H)-one that had a potent anti-HIV-1 effect. A structure-activity relationship (SAR) study using nine synthetic derivatives of aristolactam identified the differing effects of residue substitutions on the inhibition of HIV-1 infection and cell viability. Among the compounds tested, 1,2,8,9-tetramethoxy-5-(2-(piperidin-1-yl)ethyl)-dibenzo[cd,f]indol-4(5H)-one (Compound 2) exhibited the most potent activity by inhibiting HIV-1 infection with a half-maximal inhibitory concentration (IC50) of 1.03 μmol/L and a half-maximal cytotoxic concentration (CC50) of 16.91 μmol/L (selectivity index, 16.45). The inhibitory effect of the compounds on HIV-1 infection was linked to inhibition of the viral replication cycle. Mode-of-action studies showed that the aristolactam derivatives did not affect reverse transcription or integration; instead, they specifically inhibited Tat-mediated viral transcription. Taken together, these findings show that several aristolactam derivatives impaired HIV-1 infection by inhibiting the activity of Tat-mediated viral transcription, and suggest that these derivatives could be antiviral drug candidates.
Potential m6A and m5C Methylations within the Genome of A Chinese African Swine Fever Virus Strain
Lijia Jia, Jianjun Chen, Haizhou Liu, Wenhui Fan, Depeng Wang, Jing Li, Di Liu
doi: 10.1007/s12250-020-00217-2
Received: 05 January 2020 Accepted: 07 March 2020 Published: 08 August 2020
Abstract PDF Springerlink ESM
It has been more than 1 year since China reported the first case of African swine fever (ASF) infection in August 2018, and the epidemic situation remains severe (China News Service 2019). According to reports from the Ministry of Agriculture and Rural Affairs, China has reported 160 cases of ASF, which resulted in nearly 1.2 million pigs being killed, as of November 21, 2019 (China News Service 2019). ASF is an acute febrile, hemorrhagic and fulminating infectious disease, and would reach 100% case fatality rate to pigs (Gallardo et al. 2015). The causative pathogen, African swine fever virus (ASFV), is a doublestranded DNA virus with a genome of 170–193 kb belonging to the Asfarviridae family (Galindo and Alonso 2017; Gallardo et al. 2015). A recent study has revealed that ASFV maintains a core genome of 102 ORFs and has 168 dispensable genes (Wang et al. 2019). Thus, the complexed genomic features of ASFV require more attentions. By using the next generation sequencing (NGS) and the single molecule real-time sequencing (SMRT-seq), a couple of Chinese ASFV genomes have been uncovered (Bao et al. 2019; Wen et al. 2019; Jia et al. 2019). Compared to NGS, SMRT-seq has the advantage of long read length and can generate sequencing data containing the original single base modification information, which can be identified through the state-of-art bioinformatic procedures (Senol Cali et al. 2019; Simpson et al. 2017). DNA methylation is a chemical modification common in animal and plant genomes. It refers to the catalytic transfer of methyl groups on active methyl compounds (such as s-adenosine methionine) to other compounds under the catalysis of DNA methyltransferase (DNMT), mainly forming 5-methylcytosine (5-mC), 6-methyladenine (6- mA), 5-hydroxymethylcytosine (5-hmC), etc. DNA methylation, which triggers the epigenetic regulatory mechanism, has been proved to play important roles in gene expression and regulation, embryonic development, and disease-related aspects (Gouil and Keniry 2019). Whether ASFV genome has DNA methylation and epigenetic regulation is to be discerned.
A Novel Vibriophage vB_VcaS_HC Containing Lysogeny-Related Gene Has Strong Lytic Ability against Pathogenic Bacteria
Chengcheng Li, Zengmeng Wang, Jiulong Zhao, Long Wang, Guosi Xie, Jie Huang, Yongyu Zhang
doi: 10.1007/s12250-020-00271-w
Received: 02 March 2020 Accepted: 08 June 2020 Published: 07 August 2020
Abstract PDF Springerlink ESM
To avoid the negative effects of antibiotics, using phage to prevent animal disease becomes a promising method in aquaculture. Here, a lytic phage provisionally named vB_VcaS_HC that can infect the pathogen (i.e., Vibrio campbellii 18) of prawn was isolated. The phage has an isometric head and a non-contractile tail. During phage infection, the induced host mortality in 5.5 h reached ca. 96%, with a latent period of 1.5 h and a burst size of 172 PFU/cell. It has an 81,566 bp circular dsDNA genome containing 121 open reading frames (ORFs), and ca. 71% of the ORFs are functionally unknown. Comparative genomic and phylogenetic analysis revealed that it is a novel phage belonging to Delepquintavirus, Siphoviridae, Caudovirales. In the phage genome, besides the ordinary genes related to structure assembly and DNA metabolism, there are 10 auxiliary metabolic genes. For the first time, the pyruvate phosphate dikinase (PPDK) gene was found in phages whose product is a key rate-limiting enzyme involving Embden-Meyerhof-Parnas (EMP) reaction. Interestingly, although the phage has a strong bactericidal activity and contains a potential lysogeny related gene, i.e., the recombinase (RecA) gene, we did not find the phage turned into a lysogenic state. Meanwhile, the phage genome does not contain any bacterial virulence gene or antimicrobial resistance gene. This study represents the first comprehensive characterization of a lytic V. campbellii phage and indicates that it is a promising candidate for the treatment of V. campbellii infections.
SRP54 Negatively Regulates IFN-Beta Production and Antiviral Response by Targeting RIG-I and MDA5
Dong-Peng Wang, Hong-Yan Zhang, Bo-Wei Liao, Zhen Tong, Zhi-Sheng Xu, Yan-Yi Wang, Yan Yang
doi: 10.1007/s12250-020-00267-6
Received: 11 April 2020 Accepted: 08 June 2020 Published: 07 August 2020
Abstract PDF Springerlink
During virus infection, RIG-I-like receptors (RLRs) recognize viral RNAs and recruit the adaptor protein VISA to activate downstream signaling, leading to activation of transcription factors NF-κB and IRF3, which collaborate to induce type I interferons (IFNs). IFNs further induce expression of hundreds of IFN-stimulated genes (ISGs) that suppress viral replication and facilitate the adaptive immune response. Dysregulated production of IFNs is implicated in various immune diseases. Here we identified Signal Recognition Particle 54 (SRP54) as a negative regulator of RLRs-induced antiviral signaling. Overexpression of SRP54 inhibited RNA virus-triggered induction of IFN-β and increased viral replication, whereas knockdown of SRP54 had opposite effects. Mechanistically, SRP54 interacted with both RIG-I and MDA5 and impaired their association with VISA. Our findings demonstrate that SRP54 acts as a negative regulator of RLRs-mediated innate immune response by disrupting the recruitment of VISA to RIG-I/MDA5.
Immune Responses to Varicella-Zoster Virus Glycoprotein E Formulated with Poly(Lactic-co-Glycolic Acid) Nanoparticles and Nucleic Acid Adjuvants in Mice
Yunfei Wang, Jialong Qi, Han Cao, Cunbao Liu
doi: 10.1007/s12250-020-00261-y
Received: 17 April 2020 Accepted: 01 June 2020 Published: 05 August 2020
Abstract PDF Springerlink
The subunit herpes zoster vaccine Shingrix is superior to attenuated vaccine Zostavax in both safety and efficacy, yet its unlyophilizable liposome delivery system and the limited supply of naturally sourced immunological adjuvant QS-21 still need to be improved. Based on poly(lactic-co-glycolic acid) (PLGA) delivery systems that are stable during the lyophilization and rehydration process and using a double-emulsion (w/o/w) solvent evaporation method, we designed a series of nanoparticles with varicella-zoster virus antigen glycoprotein E (VZV-gE) as an antigen and nucleic acids including polyinosinic-polycytidylic acid (Poly I:C) and phosphodiester CpG oligodeoxynucleotide (CpG ODN), encapsulated as immune stimulators. While cationic lipids (DOTAP) have more potential than neutral lipids (DOPC) for activating gE-specific cell-mediated immunity (CMI) in immunized mice, especially when gE is encapsulated in and presented on the surface of nanoparticles, PLGA particles without lipids have the greatest potential to induce not only the highest gE-specific IgG titers but also the strongest gE-specific CMI responses, including the highest proportions of interferon-γ (IFN-γ)- and interleukin-2 (IL-2)-producing CD4+/CD8+T cells according to a flow cytometry assay and the greatest numbers of IFN-γ- and IL-2-producing splenocytes according to an enzyme-linked immunospot (ELISPOT) assay. These results showed that immune-stimulating nucleic acids together with the PLGA delivery system showed promise as a safe and economical varicella and zoster vaccine candidate.
Human Cytomegalovirus Influences Host circRNA Transcriptions during Productive Infection
Jingui Deng, Yujing Huang, Qing Wang, Jianming Li, Yanping Ma, Ying Qi, Zhongyang Liu, Yibo Li, Qiang Ruan
doi: 10.1007/s12250-020-00275-6
Received: 26 April 2020 Accepted: 08 July 2020 Published: 05 August 2020
Abstract PDF Springerlink ESM
Human cytomegalovirus (HCMV) is a double-strand DNA virus widely infected in human. Circular RNAs (circRNAs) are non-coding RNAs with most functions of which keep unknown, and the effects of HCMV productive infection on host circRNA transcriptions remain unclear. In this study, we profiled 283 host circRNAs that significantly altered by HCMV productive infection in human embryonic lung fibroblasts (HELF) by RNA deep sequencing and bioinformatics analysis. Among these, circSP100, circMAP3K1, circPLEKHM1, and circTRIO were validated for their transcriptions and sequences. Furthermore, characteristics of circSP100 were investigated by RT-qPCR and northern blot. It was implied that circSP100 was produced from the sense strand of the SP100 gene containing six exons. Kinetics of circSP100 and SP100 mRNA were significantly different after infection: circSP100 levels increased gradually along with infection, whereas SP100 mRNA levels increased in the beginning and dropped at 24 h post-infection (hpi). Meanwhile, a total number of 257 proteins, including 10 HCMV encoding proteins, were identified potentially binding to cytoplasmic circSP100 by RNA antisense purification (RAP) and mass spectrometry. Enrichment analysis showed these proteins were mainly involved in the spliceosome, protein processing, ribosome, and phagosome pathways, suggesting multiple functions of circSP100 during HCMV infection.
Discrimination of False Negative Results in RT-PCR Detection of SARS-CoV-2 RNAs in Clinical Specimens by Using an Internal Reference
Yafei Zhang, Changtai Wang, Mingfeng Han, Jun Ye, Yong Gao, Zhongping Liu, Tengfei He, Tuantuan Li, Mengyuan Xu, Luping Zhou, Guizhou Zou, Mengji Lu, Zhenhua Zhang
doi: 10.1007/s12250-020-00273-8
Received: 25 May 2020 Accepted: 15 July 2020 Published: 04 August 2020
Abstract PDF Springerlink ESM
Reverse transcription-polymerase chain reaction (RT-PCR) is an essential method for specific diagnosis of SARS-CoV-2 infection. Unfortunately, false negative test results are often reported. In this study, we attempted to determine the principal causes leading to false negative results of RT-PCR detection of SARS-CoV-2 RNAs in respiratory tract specimens. Multiple sputum and throat swab specimens from 161 confirmed COVID-19 patients were tested with a commercial fluorescent RT-PCR kit targeting the ORF1ab and N regions of SARS-CoV-2 genome. The RNA level of a cellular housekeeping gene ribonuclease P/MRP subunit p30 (RPP30) in these specimens was also assessed by RT-PCR. Data for a total of 1052 samples were retrospectively re-analyzed and a strong association between positive results in SARS-CoV-2 RNA tests and high level of RPP30 RNA in respiratory tract specimens was revealed. By using the ROC-AUC analysis, we identified Ct cutoff values for RPP30 RT-PCR which predicted false negative results for SARS-CoV-2 RT-PCR with high sensitivity (95.03%–95.26%) and specificity (83.72%–98.55%) for respective combination of specimen type and amplification reaction. Using these Ct cutoff values, false negative results could be reliably identified. Therefore, the presence of cellular materials, likely infected host cells, are essential for correct SARS-CoV-2 RNA detection by RT-PCR in patient specimens. RPP30 could serve as an indicator for cellular content, or a surrogate indicator for specimen quality. In addition, our results demonstrated that false negativity accounted for a vast majority of contradicting results in SARS-CoV-2 RNA test by RT-PCR.
Inception of the Modern Public Health System in China and Perspectives for Effective Control of Emerging Infectious Diseases: In Commemoration of the 140th Anniversary of the Birth of the Plague Fighter Dr. Wu Lien-Teh
Qingmeng Zhang, Niaz Ahmed, George F. Gao, Fengmin Zhang
doi: 10.1007/s12250-020-00269-4
Received: 30 January 2020 Accepted: 28 June 2020 Published: 03 August 2020
Abstract PDF Springerlink
Infectious diseases pose a serious threat to human health and affect social, economic, and cultural development. Many infectious diseases, such as severe acute respiratory syndrome (SARS, 2013), Middle East respiratory syndrome (MERS, 2012 and 2013), Zika virus infection (2007, 2013 and 2015), and coronavirus disease 2019 (COVID-19, 2019), have occurred as regional or global epidemics (Reperant and Osterhaus 2017; Gao 2018; Li et al. 2020). In the past 100 years, the world has gradually established a relatively complete modern public health system. The earliest modern public health system in China was founded by the plague fighter Dr. Wu Lien-Teh during the campaign against the plague epidemic in Northeast China from 1910 to 1911. This campaign not only played a significant part in effective control of the plague at that time, but also established a foundation for the Chinese modern public health system.
Patterns of Gustatory Recovery in Patients Affected by the COVID-19 Outbreak
Carlos M. Chiesa-Estomba, Jerome R. Lechien, Maria R. Barillari, Sven Saussez
doi: 10.1007/s12250-020-00272-9
Received: 28 June 2020 Accepted: 15 July 2020 Published: 03 August 2020
Abstract PDF Springerlink
Coronavirus disease 2019 (COVID-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). From March 2020, several studies indicate that many subjects affected by mild-to-moderate COVID-19 presented olfactory/gustatory dysfunction (OD/GD) that appeared strongly correlated between them but not with the other symptoms suggestive of upper airway infection (Lechien et al.2020a, b; Hopkins et al.2020; Paderno et al.2020).
Prediction of the Receptorome for the Human-Infecting Virome
Zheng Zhang, Sifan Ye, Aiping Wu, Taijiao Jiang, Yousong Peng
doi: 10.1007/s12250-020-00259-6
Received: 13 April 2020 Accepted: 01 June 2020 Published: 28 July 2020
Abstract PDF Springerlink
The virus receptors are key for the viral infection of host cells. Identification of the virus receptors is still challenging at present. Our previous study has shown that human virus receptor proteins have some unique features including high N-glycosylation level, high number of interaction partners and high expression level. Here, a random-forest model was built to identify human virus receptorome from human cell membrane proteins with an accepted accuracy based on the combination of the unique features of human virus receptors and protein sequences. A total of 1424 human cell membrane proteins were predicted to constitute the receptorome of the human-infecting virome. In addition, the combination of the random-forest model with protein–protein interactions between human and viruses predicted in previous studies enabled further prediction of the receptors for 693 human-infecting viruses, such as the enterovirus, norovirus and West Nile virus. Finally, the candidate alternative receptors of the SARS-CoV-2 were also predicted in this study. As far as we know, this study is the first attempt to predict the receptorome for the human-infecting virome and would greatly facilitate the identification of the receptors for viruses.
Genetic Variation of Multiple Serotypes of Enteroviruses Associated with Hand, Foot and Mouth Disease in Southern China
Yonghong Zhou, Le Van Tan, Kaiwei Luo, Qiaohong Liao, Lili Wang, Qi Qiu, Gang Zou, Ping Liu, Nguyen To Anh, Nguyen Thi Thu Hong, Min He, Xiaoman Wei, Shuanbao Yu, Tommy Tsan-Yuk Lam, Jie Cui, H. Rogier van Doorn, Hongjie Yu
doi: 10.1007/s12250-020-00266-7
Received: 12 November 2019 Accepted: 06 July 2020 Published: 28 July 2020
Abstract PDF Springerlink ESM
Enteroviruses (EVs) species A are a major public health issue in the Asia–Pacific region and cause frequent epidemics of hand, foot and mouth disease (HFMD) in China. Mild infections are common in children; however, HFMD can also cause severe illness that affects the central nervous system. To molecularly characterize EVs, a prospective HFMD virological surveillance program was performed in China between 2013 and 2016. Throat swabs, rectal swabs and stool samples were collected from suspected HFMD patients at participating hospitals. EVs were detected using generic real-time and nested reverse transcription-polymerase chain reactions (RT-PCRs). Then, the complete VP1 regions of enterovirus A71 (EV-A71), coxsackievirus A16 (CVA16) and CVA6 were sequenced to analyze amino acid changes and construct a viral molecular phylogeny. Of the 2836 enrolled HFMD patients, 2,517 (89%) were EV positive. The most frequently detected EVs were CVA16 (32.5%, 819), CVA6 (31.2%, 785), and EV-A71 (20.4%, 514). The subgenogroups CVA16_B1b, CVA6_D3a and EV-A71_C4a were predominant in China and recombination was not observed in the VP1 region. Sequence analysis revealed amino acid variations at the 30, 29 and 44 positions in the VP1 region of EV-A71, CVA16 and CVA6 (compared to the respective prototype strains BrCr, G10 and Gdula), respectively. Furthermore, in 21 of 24 (87.5%) identified EV-A71 samples, a known amino acid substitution (D31N) that may enhance neurovirulence was detected. Our study provides insights about the genetic characteristics of common HFMD-associated EVs. However, the emergence and virulence of the described mutations require further investigation.
The Multifaceted Roles of TAM Receptors during Viral Infection
Zhao-Yang Wang, Pei-Gang Wang, Jing An
doi: 10.1007/s12250-020-00264-9
Received: 18 April 2020 Accepted: 08 June 2020 Published: 27 July 2020
Abstract PDF Springerlink
Tyro3, Axl, and Mertk (TAM) receptors play multiple roles in a myriad of physiological and pathological processes, varying from promoting the phagocytic clearance of apoptotic cells, sustaining the immune and inflammatory homeostasis, maintaining the blood-brain barrier (BBB) integrity and central nervous system (CNS) homeostasis, to mediating cancer malignancy and chemoresistance. Growth arrest-specific protein 6 (Gas6) and protein S (Pros1) are the two ligands that activate TAM receptors. Recently, TAM receptors have been reported to mediate cell entry and infection of multitudinous enveloped viruses in a manner called apoptotic mimicry. Moreover, TAM receptors are revitalized during viral entry and infection, which sequesters innate immune and inflammatory responses, facilitating viral replication and immune evasion. However, accumulating evidence have now proposed that TAM receptors are not required for the infection of these viruses in vivo. In addition, TAM receptors protect mice against the CNS infection of neuroinvasive viruses and relieve the brain lesions during encephalitis. These protective effects are achieved through maintaining BBB integrity, attenuating proinflammatory cytokine production, and promoting neural cell survival. TAM receptors also regulate the programmed cell death modes of virus-infected cells, which have profound impacts on the pathogenesis and outcome of infection. Here, we systematically review the functionalities and underlying mechanisms of TAM receptors and propose the potential application of TAM agonists to prevent severe viral encephalitis.
Dynamic Changes of Antibodies to SARS-CoV-2 in COVID-19 Patients at Early Stage of Outbreak
Huaqing Shu, Shuzhen Wang, Shunan Ruan, Yaxin Wang, Jiancheng Zhang, Yin Yuan, Hong Liu, Yongran Wu, Ruiting Li, Shangwen Pan, Yaqi Ouyang, Shiying Yuan, Peng Zhou, You Shang
doi: 10.1007/s12250-020-00268-5
Received: 11 May 2020 Accepted: 15 June 2020 Published: 24 July 2020
Abstract PDF Springerlink
The coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has spread around the world with high mortality. To diagnose promptly and accurately is the vital step to effectively control its pandemic. Dynamic characteristics of SARS-CoV-2-specific antibodies which are important for diagnosis of infection have not been fully demonstrated. In this retrospective, single-center, observational study, we enrolled the initial 131 confirmed cases of COVID-19 at Jin-Yin-Tan Hospital who had at least one-time antibody tested during their hospitalization. The dynamic changes of IgM and IgG antibodies to SARS-CoV-2 nucleocapsid protein in 226 serum samples were detected by ELISA. The sensitivities of IgM and IgG ELISA detection were analyzed. Result showed that the sensitivity of the IgG ELISA detection (92.5%) was significantly higher than that of the IgM (70.8%) (P < 0.001). The meantimes of seroconversion for IgM and IgG were 6 days and 3 days, respectively. The IgM and IgG antibody levels peaked at around 18 days and 23 days, and then IgM fell to below the baseline level at about day 36, whereas IgG maintained at a relatively high level. In conclusion, antibodies should be detected to aid in diagnosis of COVID-19 infection. IgG could be a sensitive indicator for retrospective diagnosis and contact tracing, while IgM could be an indicator of early infection.
Serologic Response to SARS-CoV-2 in COVID-19 Patients with Different Severity
Wen-Hua Kong, Rong Zhao, Jun-Bo Zhou, Fang Wang, De-Guang Kong, Jian-Bin Sun, Qiong-Fang Ruan, Man-Qing Liu
doi: 10.1007/s12250-020-00270-x
Received: 31 May 2020 Accepted: 07 July 2020 Published: 23 July 2020
Abstract PDF Springerlink
The immense patient number caused by coronavirus disease 2019 (COVID-19) global pandemic brings the urge for more knowledge about its immunological features, including the profile of basic immune parameters. In this study, eighty-eight reported COVID-19 patients in Wuhan were recruited from January to February, 2020, including 32 severe/critical cases and 56 mild/moderate cases. Their mean age was 56.43 years (range 17–83) and gender ratio (male/female) was 43:45. We tested SARS-CoV-2 RNA with commercial kits, investigated the level of serologic IgM and IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using magnetic particle chemiluminescence immunoassays, and compared the results of serologic tests and nucleic acid test (NAT). Among 88 patients, 95.45% were confirmed as positive by the combination of NAT and antibody test, which was significantly higher (P < 0.001) than by single nucleic acid test (73.86%) or serologic test (65.91%). Then the correlation between temporal profile and the level of antibody response was analyzed. It showed that seroconversion started on day 5 after disease onset and IgG level was rose earlier than IgM. Comparison between patients with different disease severity suggested early seroconversion and high antibody titer were linked with less severe clinical symptoms. These results supported the combination of serologic testing and NAT in routine COVID-19 diagnosis and provided evidence on the temporal profile of antibody response in patients with different disease severity.
Mild Cytokine Elevation, Moderate CD4+ T Cell Response and Abundant Antibody Production in Children with COVID-19
Ran Jia, Xiangshi Wang, Pengcheng Liu, Xiaozhen Liang, Yanling Ge, He Tian, Hailing Chang, Hao Zhou, Mei Zeng, Jin Xu
doi: 10.1007/s12250-020-00265-8
Received: 02 July 2020 Accepted: 06 July 2020 Published: 22 July 2020
Abstract PDF Springerlink
Children with Coronavirus Disease 2019 (COVID-19) were reported to show milder symptoms and better prognosis than their adult counterparts, but the difference of immune response against SARS-CoV-2 between children and adults hasn’t been reported. Therefore we initiated this study to figure out the features of immune response in children with COVID-19. Sera and whole blood cells from 19 children with COVID-19 during different phases after disease onset were collected. The cytokine concentrations, SARS-CoV-2 S-RBD or N-specific antibodies and T cell immune responses were detected respectively. In children with COVID-19, only 3 of 12 cytokines were increased in acute sera, including interferon (IFN)-γ-induced protein 10 (IP10), interleukin (IL)-10 and IL-16. We observed an increase in T helper (Th)-2 cells and a suppression in regulatory T cells (Treg) in patients during acute phase, but no significant response was found in the IFN-γ-producing or tumor necrosis factor (TNF)-α-producing CD8+ T cells in patients. S-RBD and N IgM showed an early induction, while S-RBD and N IgG were prominently induced later in convalescent phase. Potent S-RBD IgA response was observed but N IgA seemed to be inconspicuous. Children with COVID-19 displayed an immunophenotype that is less inflammatory than adults, including unremarkable cytokine elevation, moderate CD4+ T cell response and inactive CD8+ T cell response, but their humoral immunity against SARS-CoV-2 were as strong as adults. Our finding presented immunological characteristics of children with COVID-19 and might give some clues as to why children develop less severe disease than adults.
TAR DNA-Binding Protein 43 is Cleaved by the Protease 3C of Enterovirus A71
Xiaoman Wo, Yuan Yuan, Yong Xu, Yang Chen, Yao Wang, Shuoxuan Zhao, Lexun Lin, Xiaoyan Zhong, Yan Wang, Zhaohua Zhong, Wenran Zhao
doi: 10.1007/s12250-020-00262-x
Received: 21 March 2020 Accepted: 01 June 2020 Published: 21 July 2020
Abstract PDF Springerlink ESM
Enterovirus A71 (EV-A71) is one of the etiological pathogens leading to hand, foot, and mouth disease (HFMD), which can cause severe neurological complications. The neuropathogenesis of EV-A71 infection is not well understood. The mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43) is the pathological hallmark of amyotrophic lateral sclerosis (ALS). However, whether TDP-43 was impacted by EV-A71 infection is unknown. This study demonstrated that TDP-43 was cleaved during EV-A71 infection. The cleavage of TDP-43 requires EV-A71 replication rather than the activated caspases due to viral infection. TDP-43 is cleaved by viral protease 3C between the residues 331Q and 332S, while mutated TDP-43 (Q331A) was not cleaved. In addition, mutated 3C which lacks the protease activity failed to induce TDP-43 cleavage. We also found that TDP-43 was translocated from the nucleus to the cytoplasm, and the mislocalization of TDP-43 was induced by viral protease 2A rather than 3C. Taken together, we demonstrated that TDP-43 was cleaved by viral protease and translocated to the cytoplasm during EV-A71 infection, implicating the possible involvement of TDP-43 in the pathogenesis of EV-A71infection.
A Small-Scale Medication of Leflunomide as a Treatment of COVID-19 in an Open-Label Blank-Controlled Clinical Trial
Ke Hu, Mengmei Wang, Yang Zhao, Yunting Zhang, Tao Wang, Zhishui Zheng, Xiaochen Li, Shaolin Zeng, Dong Zhao, Honglin Li, Ke Xu, Ke Lan
doi: 10.1007/s12250-020-00258-7
Received: 03 June 2020 Accepted: 16 June 2020 Published: 21 July 2020
Abstract PDF Springerlink
We recently reported that inhibitors against human dihydroorotate dehydrogenase (DHODH) have broad-spectrum antiviral activities including their inhibitory efficacies on SARS-CoV-2 replication in infected cells. However, there are limited data from clinical studies to prove the application of DHODH inhibitors in Coronavirus Disease 2019 (COVID-19) patients. In present study, we evaluated Leflunomide, an approved DHODH inhibitor widely used as a modest immune regulator to treat autoimmune diseases, in treating COVID-19 disease with a small-scale of patients. Cases of 10 laboratory-confirmed COVID-19 patients of moderate type with obvious opacity in the lung were included. Five of the patients were treated with Leflunomide, and another five were treated as blank controls without a placebo. All the patients accepted standard supportive treatment for COVID-19. The patients given Leflunomide had a shorter viral shedding time (median of 5 days) than the controls (median of 11 days, P=0.046). The patients given Leflunomide also showed a significant reduction in C-reactive protein levels, indicating that immunopathological inflammation was well controlled. No obvious adverse effects were observed in Leflunomide-treated patients, and they all discharged from the hospital faster than controls. This preliminary study on a small-scale compassionate use of Leflunomide provides clues for further understanding of Leflunomide as a potential antiviral drug against COVID-19.
Freeze-Drying Formulations Increased the Adenovirus and Poxvirus Vaccine Storage Times and Antigen Stabilities
Ye Chen, Qibin Liao, Tianyue Chen, Yuchao Zhang, Weien Yuan, Jianqing Xu, Xiaoyan Zhang
doi: 10.1007/s12250-020-00250-1
Received: 19 April 2020 Accepted: 09 June 2020 Published: 21 July 2020
Abstract PDF Springerlink
Successful vaccines induce specific immune responses and protect against various viral and bacterial infections. Noninactivated vaccines, especially viral vector vaccines such as adenovirus and poxvirus vaccines, dominate the vaccine market because their viral particles are able to replicate and proliferate in vivo and produce lasting immunity in a manner similar to natural infection. One challenge of human and livestock vaccination is vaccine stability related to the antigenicity and infectivity. Freeze-drying is the typical method to maintain virus vaccine stability, while cold chain transportation is required for temperatures about 2 ℃–8 ℃. The financial and technological resource requirements hinder vaccine distribution in underdeveloped areas. In this study, we developed a freeze-drying formula consisting of bovine serum albumin (BSA), L-glutamic acid (L-Glu), polyethylene glycol (PEG), and dextran (DEX) to improve the thermal stability and activity of viral vaccines, including vaccinia recombinant vaccine (rTTV-OVA) and adenovirus vaccine (Ad5-ENV). We compared a panel of five different formulations (PEG: DEX: BSA: L-GLU=50:9:0:0(#1), 50:5:4:0(#2), 50:10:9:0(#3), 50:0:0:9(#4), and 50:1:0:8(#5), respectively) and optimized the freeze-drying formula for rTTV-OVA and Ad5-ENV. We found that the freeze-drying formulations #2 and #3 could maintain rTTV-OVA infectivity at temperatures of 4 ℃ and 25 ℃ and that rTTV-OVA immunogenicity was retained during lyophilization. However, formulations #4 and #5 maintained Ad5-ENV infectivity under the same conditions, and Ad5-ENV immunogenicity had maximum retention with freeze-drying formulation #4. In summary, we developed new freeze-drying formulations that increased virus vaccine storage times and retained immunogenicity at an ambient temperature.
Identification, Isolation, and Characterization of an Ectromelia Virus New Strain from an Experimental Mouse
Jun Wang, Xiaoping Liu, Qiong Zhu, Qiaoli Wu, Shuang Tang, Lei Zhang, Zhaojun Fan, Zhihong Hu, Hualin Wang, Fei Deng, Shu Shen
doi: 10.1007/s12250-020-00263-w
Received: 17 January 2020 Accepted: 15 June 2020 Published: 21 July 2020
Abstract PDF Springerlink ESM
Ectromelia virus (ECTV) is a large double-stranded DNA virus belonging to the genus Orthopoxviruses in the family Poxviridae. It is the causative agent of mousepox, which is a lethal, acute toxic disease with high mortality rate in most strains of laboratory mice. It was first discovered in 1930 when mice were first used as animal models (Marchal 1930). It has long been enzootic in laboratory mouse colonies in Europe, Japan, and China, and later spread to USA (Fenner 1981; Esteban and Buller 2005). To date, there are four ECTV strains with complete genome sequences deposited in GenBank. ECTV strain Hampstead (ECTV-Ham) was the first discovered strain from a laboratory mouse colony in London (Marchal 1930). ECTV strain Moscow (ECTV-Mos) derived from Moscow was considered more virulent than ECTV-Ham based on animal experiments (Andrewes and Elford 1947). ECTV strain Naval (ECTV-Nav) was isolated from an outbreak at the Naval Medical Research Institute in Bethesda, MD (Dick et al. 1996). ECTV strain culture-collection ATCC VR-1431 (ECTV-ATCC) was isolated from throat swabs of six individuals who were suffering from erythromelalgia in rural China in 1987. This virus was referred as erythromelalgia-associated poxvirus as indicated by serological tests and viral morphology (Zheng et al. 1992). By next generation sequencing in 2012, the virus was finally identified a new ECTV strain closely related to strains ECTV-Mos and ECTV-Nav (Mendez-Rios et al. 2012).
Identification and Molecular Characterization of a New Omono River Virus Isolated from Culex Tritaeniorhynchus in Yunnan, China
Yawei Zhang, Xin Qiang, Xiaofang Guo, Honghong Peng, Si Qin, Yujun Cui, Hang Fan, Hongning Zhou, Jiusong Zhang, Jinglin Wang, Yigang Tong
doi: 10.1007/s12250-020-00247-w
Received: 17 January 2020 Accepted: 28 April 2020 Published: 20 July 2020
Abstract PDF Springerlink ESM
The family Totiviridae contains non-enveloped, double-stranded RNA viruses with genomes of approximately 4.6–7 kbp in length. These totiviruses are classified into five genera: Totivirus, Victorivirus, Trichomonasvirus, Giardiavirus, and Leishmaniavirus (Nibert 2007). They are associated with latent infections of fungal or protozoan hosts (Li et al. 2020). Recently, a few totiviruses have been identified and shown to have unexpected host distributions, including insects, plants, and even Chromalveolata (Chen et al. 2016; Koyama et al. 2015; Marchler-Bauer et al. 2017; Mor and Phelps 2016). However, most of these new viruses have not been assigned to appropriate genera by the International Committee on Taxonomy of Viruses (ICTV). Omono River virus (ORV) is an unclassified RNA virus in the family Totiviridae (Isawa et al. 2011; Okamoto et al. 2016). In this study, we reported a novel ORV isolated from a pool of Culex tritaeniorhynchus mosquitoes collected in Yunnan, China. We also updated the phylogenetic relationships of the family Totiviridae to include all genomes reported to date.
Perinatal Vertical Transmission of Chikungunya Virus in Ruili, a Town on the Border between China and Burma
Jia-Yuan Shen, Man Li, Lyu Xie, Jia-Rong Mao, Hong-Ning Zhou, Pei-Gang Wang, Jin-Yong Jiang, Jing An
doi: 10.1007/s12250-020-00245-y
Received: 20 January 2020 Accepted: 18 May 2020 Published: 16 July 2020
Abstract PDF Springerlink
Chikungunya virus (CHIKV), an arbovirus in the family of Togaviridae, genus Alphavirus, is transmitted by the A. aegyptii or A. albopictus mosquito, and causes disease in humans characterized by fever, rash, and arthralgia (Silva and Dermody 2017; Suhrbier 2019). It was first reported in 1953 in Tanzania, and caused only a few outbreaks and sporadic cases in Africa and Asia in last century. However, in the epidemic in 2004, CHIKV acquired mutations that conferred enhanced transmission by the A. albopictus mosquito (Schuffenecker et al. 2006). Since then, it has successively caused outbreaks in Africa, the Indian Ocean, South East Asia, the South America, and Europe (Zeller et al. 2016).
The Prevalence, Genetic Characterization, and Evolutionary Analysis of Porcine Pegivirus in Guangdong, China
Yongsheng Xie, Xiaoru Wang, Junsen Feng, Liuming Wei, Gen Li, Guangbin Si, Yibo Chen, He Yan, Dongsheng He
doi: 10.1007/s12250-020-00240-3
Received: 07 December 2019 Accepted: 15 April 2020 Published: 08 July 2020
Abstract PDF Springerlink ESM
Porcine pegivirus (PPgV) is a member of the Pegivirus genus in the Flaviviridae family. PPgV is an emerging virus that has been discovered in swine herds in Germany, the United States, China, Poland, Italy, and the United Kingdom, indicating a wide geographical distribution. In this retrospective study, 339 pig serum samples were collected from 20 different commercial swine farms located in nine cities in Guangdong Province, China, from 2016 to 2018, to investigate the prevalence and genetic diversity of PPgV in this geographical region. PPgV was detected in 55% (11/20) of the farms using nested reverse transcription PCR, with 6.2% (21/339) of pigs testing positive for PPgV. The yearly PPgV-positive rate increased from 2.6% to 7.5% between 2016 and 2018. Sequencing of PPgV-positive samples identified two complete polyprotein genes and seven partial NS5B genes from different farms. Comparative analysis of the polyprotein genes revealed that PPgV sequences obtained in this study showed 87.4%–97.2% similarity at the nucleotide level and 96.5%– 99.4% similarity at the amino acid level with the reference sequences. Sequence alignment and phylogenetic analysis of the complete polyprotein gene and partial NS5B and NS3 genes demonstrated a high genetic similarity with the samples from the USA. The finding of the wide distribution of PPgV in swine herds in Guangdong Province will contribute to the understanding of the epidemiological characteristics and genetic evolution of PPgV in China.
Feasibility Study of Mixing Throat Swab Samples for Severe Acute Respiratory Syndrome Coronavirus-2 Screening
Yang Han, Qingyu Yang, Ying Liu, Ting Shu, Li Yue, Ting Xiao, Qin Zeng, Ying Wu, Xi Zhou, Dingyu Zhang
doi: 10.1007/s12250-020-00254-x
Received: 12 May 2020 Accepted: 03 June 2020 Published: 08 July 2020
Abstract PDF Springerlink
The outbreak of coronavirus disease 2019 (COVID-19) has been declared a pandemic by the World Health Organization (WHO) and has resulted in the worst public health crisis since World War Ⅱ (Wang et al. 2020). The causative pathogen of COVID-19 is a novel strain of coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2); SARS-CoV-2 is the seventh coronavirus that has been found to infect humans (Gorbalenya et al. 2020; Zhang and Holmes 2020; Zhu et al. 2020). As of June 8, 2020, more than 7 million confirmed cases of COVID-19 have been reported worldwide, resulting in approximately 400,000 deaths (WHO 2020). As recommended by the WHO, detection and isolation are essential for containing the rapid spread of this pandemic. Therefore, adequate, large-scale screening and detection of SARS-CoV-2 are necessary. In addition, in locations in which the population has experienced and gradually recovered from COVID-19, there may be a huge demand for large-scale testing and surveillance. For example, in Wuhan city, in which the virus was successfully contained after its rapid spread, residents gradually resumed normal activities beginning in mid-March, with full re-opening of the economy by April 8, 2020. Data from Wuhan Municipal Health Commission showed that approximately 275,400 nucleic acid tests for SARS-CoV-2 had been conducted for people who returned to work in Wuhan from April 8 to April 15 (CCTV 2020). Therefore, all countries and cities, including those still experiencing outbreaks and those in the process of recovery, are expected to require mass COVID-19 testing, which could be limited by worldwide testing capacity.
Epidemiology and Genotypic Diversity of Eurasian Avian-Like H1N1 Swine Influenza Viruses in China
Zhaomin Feng, Wenfei Zhu, Lei Yang, Jia Liu, Lijuan Zhou, Dayan Wang, Yuelong Shu
doi: 10.1007/s12250-020-00257-8
Received: 24 April 2020 Accepted: 10 June 2020 Published: 07 July 2020
Abstract PDF Springerlink ESM
Eurasian avian-like H1N1 (EA H1N1) swine influenza virus (SIV) outside European countries was first detected in Hong Kong Special Administrative Region (Hong Kong, SAR) of China in 2001. Afterwards, EA H1N1 SIVs have become predominant in pig population in this country. However, the epidemiology and genotypic diversity of EA H1N1 SIVs in China are still unknown. Here, we collected the EA H1N1 SIVs sequences from China between 2001 and 2018 and analyzed the epidemic and phylogenic features, and key molecular markers of these EA H1N1 SIVs. Our results showed that EA H1N1 SIVs distributed in nineteen provinces/municipalities of China. After a long-time evolution and transmission, EA H1N1 SIVs were continuously reassorted with other co-circulated influenza viruses, including 2009 pandemic H1N1 (A(H1N1)pdm09), and triple reassortment H1N2 (TR H1N2) influenza viruses, generated 11 genotypes. Genotype 3 and 5, both of which were the reassortments among EA H1N1, A(H1N1)pdm09 and TR H1N2 viruses with different origins of M genes, have become predominant in pig population. Furthermore, key molecular signatures were identified in EA H1N1 SIVs. Our study has drawn a genotypic diversity image of EA H1N1 viruses, and could help to evaluate the potential risk of EA H1N1 for pandemic preparedness and response.
Controversial: Early Innate Responses to Hepatitis B Virus Infection, an Explanation for Viral Persistence?
Ruth Broering, Xufeng Luo, Jia Liu, Mengji Lu
doi: 10.1007/s12250-020-00235-0
Received: 11 February 2020 Accepted: 03 April 2020 Published: 06 July 2020
Abstract PDF Springerlink
Hepatitis B virus (HBV) infection is one of the most common causes for liver related morbidity and mortality worldwide. Liver fibrosis and cirrhosis occur in the course of chronic HBV infection, with the increasing risk to develop hepatocellular carcinoma. In about 95% of adults' acute hepatitis B virus infection is self-limited, whereas in 90% of young children HBV infection leads to chronic progression. It is likely that a fully developed immune system contributes to HBV clearance (Dandri and Locarnini 2012; Bertoletti and Kennedy 2015). However, investigations of acute HBV infection in chimpanzees revealed a lack of any inducible immune genes related to viral entry and replication at early time points (Wieland et al. 2004). It has been suggested that HBV may not be recognized by the immune system and therefore has been described as stealth virus. However, the viral clearance phase is accompanied by the expression of genes related to T lymphocyte and interferon (IFN)-gamma responses. Assuming, that HBV-specific CD8 T cell effector functions and an appropriate CD4 T cell response can lead to viral clearance (Wieland and Chisari 2005). The stealth properties of HBV have recently been questioned, and it has been shown that in the early phase of infection primary human hepatocytes (PHH) sense HBV particles via toll-like receptor 2 (TLR2) (Zhang et al. 2020). This leads to the production of inflammatory cytokines including interleukin 6 (IL6) and tumour necrosis factor (TNF) which are able to suppress HBV replication in an interferon-independent manner (Hosel et al. 2009; Zhang et al. 2012). TLR2 activation has also been described for Kupffer cells/macrophages exposed to HBV particles in vitro (Cheng et al. 2017; Song et al. 2019; Zhang et al. 2020). This hepatic innate response results in cytokine and chemokine secretion that on the one hand may limit HBV replication and on the other hand orchestrates adaptive immune responses in the early phase of infection.
Recovery and Genetic Characterization of a West Nile Virus Isolate from China
Yan Guo, Hongjiang Wang, Songtao Xu, Hangyu Zhou, Chao Zhou, Shihong Fu, Mengli Cheng, Fan Li, Yongqiang Deng, Xiaofeng Li, Huanyu Wang, Cheng-Feng Qin
doi: 10.1007/s12250-020-00246-x
Received: 09 May 2020 Accepted: 25 May 2020 Published: 06 July 2020
Abstract PDF Springerlink ESM
West Nile virus (WNV) is an important neurotropic flavivirus that is widely distributed globally. WNV strain XJ11129 was first isolated in Xinjiang, China, and its genetic and biological characteristics remain largely unknown. In this study, phylogenetic and sequence analyses revealed that XJ11129 belongs to lineage 1a and shares high genetic identity with the highly pathogenic strain NY99. Then, the full-length genomic cDNA of XJ11129 was amplified and assembled using a modified Gibson assembly (GA) method. The virus (named rXJ11129) was successfully rescued in days following this method. Compared with other wild-type WNV isolates, rXJ11129 exhibited virulence indistinguishable from that of the NY99 strain in vivo. In summary, the genomic and virulence phenotypes of rXJ11129 were characterized in vivo and in vitro, and these data will improve the understanding of the spread and pathogenesis of this reemerging virus.
GTPase Activity of MxB Contributes to Its Nuclear Location, Interaction with Nucleoporins and Anti-HIV-1 Activity
Linlin Xie, Zhao Ju, Chaojie Zhong, Yingjun Wu, Yuxing Zan, Wei Hou, Yong Feng
doi: 10.1007/s12250-020-00249-8
Received: 08 March 2020 Accepted: 27 April 2020 Published: 06 July 2020
Abstract PDF Springerlink
The human myxovirus resistance 2 (Mx2/MxB) protein, a member of interferon (IFN)-inducible dynamin-like large GTPases, restricts a number of virus infections. Inhibition of these viruses occurs at poorly-defined steps after viral entry and has a common requirement for MxB oligomerization. However, the GTPase activity is essential for the anti-viral effects of MxB against herpesviruses and HBV but not HIV-1. To understand the role of MxB GTPase activity, including GTP binding and GTP hydrolysis, in restriction of HIV-1 infection, we genetically separated these two functions and evaluated their contributions to restriction. We found that both the GTP binding and hydrolysis function of MxB involved in the restriction of HIV-1 replication. The GTPase activity of MxB contributed to its nuclear location, interaction with nucleoporins (NUPs) and HIV-1 capsids. Furthermore, MxB disrupted the association between NUPs and HIV-1 cores dependently upon its GTPase activity. The function of GTPase activity was therefore multi-faceted, led to fundamentally distinct mechanisms employed by wild-type MxB and GTPase activity defective MxB mutations to restrict HIV-1 replication.
Differential CircRNA Expression Profiles in PK-15 Cells Infected with Pseudorabies Virus Type II
Haimin Li, Wen Tang, Yulan Jin, Weiren Dong, Yan Yan, Jiyong Zhou
doi: 10.1007/s12250-020-00255-w
Received: 08 November 2019 Accepted: 26 May 2020 Published: 02 July 2020
Abstract PDF Springerlink ESM
Circular RNAs (circRNAs) belong to a class of non-coding RNAs with diverse biological functions. However, little is known about their roles in case of pseudorabies virus (PrV) infection. Here, we analyzed the expression profile of host circRNAs from a virulent PrV type II strain DX (PrV-DX) infected and an attenuated gE/TK deficient (gE-TK-PrV) strain of PrV infected PK-15 cells. CircRNAs were identified by find_circ and analyzed with DESeq 2. Compared with the mock cells, 449 differentially expressed (DE) circRNAs (233 down-regulated and 216 up-regulated) from PrV-DX infected and 578 DE circRNAs (331 down-regulated and 247 up-regulated) from gE-TK-PrV infected PK-15 cells were identified. In addition, 459 DE circRNAs (164 down-regulated and 295 up-regulated) between the PrV-DX and gE-TK-PrV infected cells were identified. The expression patterns of 13 circRNAs were validated by reverse transcription quantitative real-time PCR (RT-qPCR) and results were similar as of RNA-seq. The putative target miRNA binding sites of DE circRNAs were predicted by using miRanda and psRobot. The circRNA-miRNA-mRNA network was constructed and certain miRNAs that have possible roles in antiviral immune response, such as miR-210 and miR-340, were predicted. GO and KEGG pathway analysis demonstrated that DE circRNAs were enriched in the processes such as cellular metabolism, protein binding, RNA degradation and regulation of actin cytoskeleton. Collectively, these findings might provide the useful information for a better understanding of mechanisms underlying the interaction between PrV-II and host cells.
Novel HCV-Like Virus Detected in Avian Livers in Southern China and Its Implications for Natural Recombination Events
Gang Lu, Jiawei Zhao, Jiajun Ou, Shoujun Li
doi: 10.1007/s12250-020-00256-9
Received: 12 March 2020 Accepted: 26 April 2020 Published: 02 July 2020
Abstract PDF Springerlink ESM
Hepacivirus C virus (HCV) is a major cause of liver disease in human, which is estimated to infect 2%–3% of the world’s population and has resulted in a high global health burden. HCV was first discovered in 1989, and was the sole member of the Hepacivirus genus before 2011. Recently, genetically-diverse HCV-like viruses have been independently determined in a number of animal species, expending the members of the genus Hepacivirus to 14 species (Hepacivirus AN) as recommended by International Committee on Taxonomy of Viruses (ICTV) (Hartlage et al. 2016; Smith et al. 2016).
Emergence of Zika Virus in Culex tritaeniorhynchus and Anopheles sinensis Mosquitoes in China
Jing Wang, Hongbin Xu, Song Song, Rui Cheng, Na Fan, Shihong Fu, Shaozai Zhang, Ziqian Xu, Ying He, Wenwen Lei, Fan Li, Huanyu Wang, Xiaoqing Lu, Guodong Liang
doi: 10.1007/s12250-020-00239-w
Received: 11 October 2019 Accepted: 08 April 2020 Published: 02 July 2020
Abstract PDF Springerlink ESM
Zika virus (ZIKV) has been isolated from mosquitoes such as Aedes, Mansonia uniformis, and Culex perfuscus; However, the isolation of ZIKV from Anopheles sinensis and Culex tritaeniorhynchus has not yet been reported. In June and July 2018, 22,985 mosquitoes and 57,500 midges were collected in Jiangxi Province in southeastern China. Among them, six strains of ZIKV were isolated from mosquitoes: four from An. sinensis and two from Cx. tritaeniorhynchus. Molecular genetic analysis showed that the ZIKV isolated from An. sinensis and Cx. tritaeniorhynchus belonged to genotype 2 in the Asian evolutionary branch of ZIKV. In addition, the ZIKV strains isolated from An. sinensis and Cx. tritaeniorhynchus had amino acid substitutions identical to ZIKV strains prevalent in South America since 2015. This study is the first to isolate ZIKV from mosquito specimens collected in the wild of Jiangxi Province, China; This is also the first time that ZIKV has been isolated from An. sinensis and Cx. tritaeniorhynchus. Given that An. sinensis and Cx. tritaeniorhynchus have a very wide geographical distribution in China and even in eastern and southern Asia, the isolation of several strains of ZIKV from these two mosquitoes poses new challenges for the prevention and control of ZIKV infection in the mainland of China and countries and regions with the same distribution of mosquitoes.
Monitoring Neutralization Property Change of Evolving Hantaan and Seoul Viruses with a Novel Pseudovirus-Based Assay
Tingting Ning, Ling Wang, Shuo Liu, Jian Ma, Jianhui Nie, Weijin Huang, Xuguang Li, Yuhua Li, Youchun Wang
doi: 10.1007/s12250-020-00237-y
Received: 20 December 2019 Accepted: 03 April 2020 Published: 12 June 2020
Abstract PDF Springerlink ESM
The Hantaan virus (HTNV) and Seoul virus (SEOV) mutants have accumulated over time. It is important to determine whether their neutralizing epitopes have evolved, thereby making the current vaccine powerless. However, it is impossible to determine by using traditional plaque reduction neutralization test (PRNT), because it requires large numbers of live mutant strains. Pseudovirus-based neutralization assays (PBNA) were developed by employing vesicular stomatitis virus (VSV) backbone incorporated with HTNV or SEOV glycoproteins (VSVΔG*-HTNVG or VSVΔG*-SEOVG). 56 and 51 single amino acid substitutions of glycoprotein (GP) in HTNV and SEOV were selected and introduced into the reference plasmid. Then the mutant pseudoviruses were generated and tested by PBNA. The PBNA results were highly correlated with PRNT ones with R2 being 0.91 for VSVΔG*-HTNVG and 0.82 for VSVΔG*-SEOVG. 53 HTNV mutant pseudoviruses and 46 SEOV mutants were successfully generated. Importantly, by using PBNA, we found that HTNV or SEOV immunized antisera could neutralize all the corresponding 53 HTNV mutants or the 46 SEOV mutants respectively. The novel PBNA enables us to closely monitor the effectiveness of vaccines against large numbers of evolving HTNV and SEOV. And the current vaccine remains to be effective for the naturally occurring mutants.
Fur Seal Feces-Associated Circular DNA Virus Identified in Pigs in Anhui, China
Zhibin Shi, Chunguo Liu, Huanliang Yang, Yan Chen, Hua Liu, Lili Wei, Zaisi Liu, Yongping Jiang, Xijun He, Jingfei Wang
doi: 10.1007/s12250-020-00232-3
Received: 11 October 2019 Accepted: 07 March 2020 Published: 02 June 2020
Abstract PDF Springerlink ESM
Fur seal feces-associated circular DNA virus (FSfaCV) is an unclassified circular replication-associated protein (Rep)-encoding single-stranded (CRESS) DNA virus that has been detected in mammals (fur seals and pigs). The biology and epidemiology of the virus remain largely unknown. To investigate the virus diversity among pigs in Anhui Province, China, we pooled 600 nasal samples in 2017 and detected viruses using viral metagenomic methods. From the assembled contigs, 12 showed notably high nucleotide acid sequence similarities to the genome sequences of FSfaCVs. Based on these sequences, a full-length genome sequence of the virus was then obtained using overlapping PCR and sequencing, and the virus was designated as FSfaCV-CHN (GenBank No. MK462122). This virus shared 91.3% and 90.9% genome-wide nucleotide sequence similarities with the New Zealand fur seal strain FSfaCV-as50 and the Japanese pig strain FSfaCV-JPN1, respectively. It also clustered with the two previously identified FSfaCVs in a unique branch in the phylogenetic tree based on the open reading frame 2 (ORF2), Rep-coding gene, and the genome of the reference CRESS DNA viruses. Further epidemiological investigation using samples collected in 2018 showed that the overall positive rate for the virus was 56.4% (111/197) in Anhui Province. This is the first report of FSfaCVs identified in pigs in China, and further epidemiological studies are warranted to evaluate the influence of the virus on pigs.
Concerns on Vaccine against Varicella Caused by Varicella-Zoster Virus Infection
Wen-Bo Zeng, Fukun Zhang, Shuang Cheng, Jin-yan Sun, Hongjie Shen, Min-Hua Luo
doi: 10.1007/s12250-020-00231-4
Received: 08 January 2020 Accepted: 17 April 2020 Published: 28 May 2020
Abstract PDF Springerlink
Varicella-zoster virus (VZV) belongs to a neurotropic Alphaherpesvirinae and is the causative pathogen of both the varicella and herpes zoster. Currently, there are three different vaccines for the prevention, low does live-attenuated Oka (vOka) against varicella, high does vOka and glycoprotein E with the AS01B adjuvant system against zoster. Varicella vaccine containing vOka effectively prevents varicella, but latency of vOka can be detected in the inoculated population and its reactivation causes zoster. Reducing virulence of vOka is a potential way to prevent vOka reactivation from latency, or transport from infected neuron to neighbor neurons and the innervated dermatome, which causes herpes zoster. Therefore, to develop better/ safer vaccine that can not only prevent varicella, but also avoid herpes zoster is required. In addition, change onedose varicella vaccination to two-dose schedule will help to prevent varicella breakouts in primary schools.
On the Calculation of TCID50 for Quantitation of Virus Infectivity
Chengfeng Lei, Jian Yang, Jia Hu, Xiulian Sun
doi: 10.1007/s12250-020-00230-5
Received: 10 March 2020 Accepted: 15 April 2020 Published: 26 May 2020
Abstract PDF Springerlink ESM
The most important property of a virus is its infectivity. To measure infectivity, one can assay viral replication in cells to obtain a titer for a given virus stock. A titer is defined as a given number of infectious viral units per unit volume, and an infectious unit is the smallest amount of virus that produces recognizable effects [e.g., cytopathic effect (CPE), dot blot immunoreactivity]. The median tissue culture infectious dose (TCID50) is defined as the dilution of a virus required to infect 50% of a given cell culture.
First Fatal Infection and Phylodynamic Analysis of Severe Fever with Thrombocytopenia Syndrome Virus in Jilin Province, Northeastern China
Xu Zhang, Nina Wang, Zedong Wang, Lihe Che, Chen Chen, Wen-Zhong Zhao, Quan Liu
doi: 10.1007/s12250-020-00228-z
Received: 30 October 2019 Accepted: 16 March 2020 Published: 26 May 2020
Abstract PDF Springerlink ESM
Severe fever with thrombocytopenia syndrome (SFTS), caused by SFTS virus (SFTSV) in the genus Banyangvirus of the family Phenuiviridae, is an emerging tick-borne viral zoonosis (Liu et al. 2014). Typical clinical symptoms of SFTS include fever, headache, thrombocytopenia, and leukocytopenia (Yu et al. 2011). Since SFTSV was identified in 2009, it has been found in more than 20 provinces in China and is closely related to strains from Japan and South Korea (Kim et al. 2013; Takahashi et al. 2014). In Northeastern China, the disease was discovered in Liaoning Province in 2010 (Wang et al. 2016), and the virus was detected in Haemaphysalis longicornis in Jilin Province in 2013 (Liu et al. 2016). Here we describe the first fatal case of SFTS in Jilin Province and conduct phylodynamic analysis of SFTSV.
Construction and Characterization of a Novel Recombinant Attenuated and Replication-Deficient Candidate Human Adenovirus Type 3 Vaccine: “Adenovirus Vaccine Within an Adenovirus Vector”
Yuqian Yan, Shuping Jing, Liqiang Feng, Jing Zhang, Zhiwei Zeng, Min Li, Shan Zhao, Junxian Ou, Wendong Lan, Wenyi Guan, Xiaowei Wu, Jianguo Wu, Donald Seto, Qiwei Zhang
doi: 10.1007/s12250-020-00234-1
Received: 22 February 2020 Accepted: 13 April 2020 Published: 26 May 2020
Abstract PDF Springerlink
Human adenoviruses (HAdVs) are highly contagious and result in large number of acute respiratory disease (ARD) cases with severe morbidity and mortality. Human adenovirus type 3 (HAdV-3) is the most common type that causes ARD outbreaks in Asia, Europe,andtheAmericas.However,thereiscurrentlynovaccineapprovedforitsgeneraluse.Thehexonproteincontainsthemain neutralizing epitopes, provoking strong and lasting immunogenicity. In this study, a novel recombinant and attenuated adenovirus vaccine candidate against HAdV-3 was constructed based on a commercially-available replication-defective HAdV-5 gene therapy and vaccine vector. The entire HAdV-3 hexon gene was integrated into the E1 region of the vector by homologous recombination using a bacterial system. Theresultantrecombinants expressing the HAdV-3 hexon protein were rescued in AD293 cells, identified and characterized by RT-PCR, Western blots, indirect immunofluorescence, and electron microscopy. This potential vaccine candidate had a similar replicative efficacy as the wild-type HAdV-3 strain. However, and importantly, the vaccine strain had been rendered replication-defective and was incapable of replication in A549 cells after more than twenty-generation passages in AD293 cells. This represents a significant safety feature. The mice immunized both intranasally and intramuscularly by this vaccine candidate raised significant neutralizing antibodies against HAdV-3. Therefore, this recombinant, attenuated, and safe adenovirus vaccine is a promising HAdV-3 vaccine candidate. The strategy of using a clinically approved and replication-defective HAdV-5 vector provides a novel approach to develop universal adenovirus vaccine candidates against all the other types of adenoviruses causing ARDs and perhaps other adenovirus-associated diseases.


A Comprehensive Review on Human Aichi Virus
Enrique Rivadulla, Jesús L. Romalde
2020, 35(5): 501-516.  doi: 10.1007/s12250-020-00222-5
Received: 21 September 2019 Accepted: 28 February 2020 Published: 27 April 2020
HTML Full Text [PDF 1292KB] Springerlink
Although norovirus, rotavirus, adenovirus and Astrovirus are considered the most important viral agents transmitted by food and water, in recent years other viruses, such as Aichi virus (AiV), have emerged as responsible for gastroenteritis outbreaks associated with different foods. AiV belongs to the genus Kobuvirus of the family Picornaviridae. It is a virus with icosahedral morphology that presents a single stranded RNA genome with positive sense (8280 nucleotides) and a poly (A) chain. AiV was first detected from clinical samples and in recent years has been involved in acute gastroenteritis outbreaks from different world regions. Furthermore, several studies conducted in Japan, Germany, France, Tunisia and Spain showed a high prevalence of AiV antibodies in adults (between 80% and 99%), which is indicative of a large exposure to this virus. The aim of this review is to bring together all the discovered information about the emerging pathogen human Aichi virus (AiV), discussing the possibles routes of transmission, new detection techniques and future research. Although AiV is responsible for a low percentage of gastroenteritis outbreaks, the high seroprevalence shown by human populations indicates an evident role as an enteric agent. The low percentage of AiV detection could be explained by the fact that the pathogen is more associated to subclinical infections. Further studies will be needed to clarify the real impact of AiV in human health and its importance as a causative gastroenteritis agent worldwide.
Research Article
Isolation and Characterization of A Novel Fowl Adenovirus Serotype 8a Strain from China
Li Chen, Lijuan Yin, Peng Peng, Qingfeng Zhou, Yunping Du, Yun Zhang, Chunyi Xue, Yongchang Cao
2020, 35(5): 517-527.  doi: 10.1007/s12250-019-00172-7
Received: 04 June 2019 Accepted: 05 August 2019 Published: 02 December 2020
HTML Full Text [PDF 5013KB] Springerlink ESM
Since 2012, the clinical cases of inclusion body hepatitis showed an increasing trend in China, causing considerable economic losses to the poultry industry. In this study, a fowl adenovirus strain CH/GDLZ/201801 was isolated from a chicken flock experiencing inclusion body hepatitis and analyzed by complete genome sequencing. The pathogenicity of the new virus strain was examined by experimental infection of specific pathogen free chickens. The isolate was identified by immunofluorescence and the virions presented typical icosahedral particles under transmission electron microscopy. The full genome of the isolate was 44, 329 nucleotides in length with 58% G+C content. Phylogenetic analysis, based on the whole genome, revealed that the new isolate was closest to serotype 8a from the species Fowl aviadenovirus E (FAdV-E). Recombination analysis and phylogenetic analysis showed that the new isolate is a recombinant strain between FAdV-8a and FAdV-8b. In infection experiments, three infected chickens showed clinical signs and one chicken died on day 7 post infection, corresponding to 5% mortality. Macroscopic and microscopic lesions in the liver were observed, and viral antigen could be detected in the livers by immunohistochemical staining and TEM. Taken together, our study describes the genomic characteristics and pathogenicity of a FAdV-8a strain in China. It would lay a solid foundation for further study of the pathogenic mechanism and vaccine development of the virus.
Characterization of the First Genome of Porcine mastadenovirus B (HNU1 Strain) and Implications on Its Lymphoid and Special Origin
Shu-Jing Liu, Qiong Wang, Ting-Ting Li, Si-Hua Zhang, Jin-Yan Li, Li-Jun Wu, Ye Qiu, Xing-Yi Ge
2020, 35(5): 528-537.  doi: 10.1007/s12250-020-00210-9
Received: 05 December 2019 Accepted: 04 February 2020 Published: 31 March 2020
HTML Full Text [PDF 4988KB] Springerlink
Porcine adenoviruses (PAdVs) are classified into three species, PAdV-A, PAdV-B, and PAdV-C. The genomes of PAdV-A and PAdV-C have been well characterized. However, the genome of PAdV-B has never been completely sequenced, and the epidemiology of PAdV-B remains unclear. In our study, we have identified a novel strain of PAdV-B, named PAdV-B-HNU1, in porcine samples collected in China by viral metagenomic assay and general PCR. The genome of PAdV-B-HNU1 is 31, 743 bp in length and highly similar to that of California sea lion adenovirus 1 (C. sea lion AdV-1), which contains typical mastadenoviral structures and some unique regions at the carboxy-terminal end. Especially, PAdV-B-HNU1 harbors a dUTPase coding region not clustering with other mastadenoviruses except for C. sea lion AdV-1 and a fiber coding region homologous with galectin 4 and 9 of animals. However, the variance of GC contents between PAdV-B-HNU1 (55%) and C. sea lion AdV-1 (36%) indicates their differential evolutionary paths. Further epidemiologic study revealed a high positive rate (51.7%) of PAdV-B-HNU1 in porcine lymph samples, but low positive rates of 10.2% and 16.1% in oral swabs and rectal swabs, respectively. In conclusion, this study characterized a novel representative genome of a lymphotropic PAdV-B with unique evolutionary origin, which contributes to the taxonomical and pathogenic studies of PAdVs.
Laos is Affected by HIV CRF01_AE and the Newly Identified CRF97_01B
Xin Chen, Mei Ye, Yu Wang, Chiyu Zhang, Yong-Tang Zheng
2020, 35(5): 538-547.  doi: 10.1007/s12250-020-00215-4
Received: 02 December 2019 Accepted: 18 February 2020 Published: 30 March 2020
HTML Full Text [PDF 2637KB] Springerlink ESM
Laos is the only landlocked country in Southeast Asia and borders Thailand, Myanmar and Cambodia, the three countries in this region that have been hardest hit by human immunodeficiency virus (HIV). Laos has been regarded as a low-HIV-prevalence country for decades. To understand the status of HIV in Laos in recent years, a retrospective study was performed among 2851 patients visiting a hospital in Vientiane, the capital of Laos, from November 2011 to May 2012. Whole blood samples were obtained from the patients, and DNA was extracted. HIV status was determined by HIV gag fragment-specific PCR assay. Sixty-nine samples were detected as HIV proviral DNA positive with a positive rate of 2.4% (69/2851). Sixty-one near full-length genomic sequences were obtained from the positive samples. The results of phylogenetic analysis showed that the vast majority (91.8%) of the HIV strains belonged to CRF01_AE, and the other five (8.2%) strains were identified as a new HIV circulating recombinant form CRF97_01B, which had a CRF01_AE backbone with an insertion of subtype B in the gag-pol region. Phylogeographic analysis revealed that HIV CRF01_AE circulating in Laos were multiply introduced from Thailand. These results indicated that Laos might be suffering a considerably more serious impact of HIV than previously believed. To keep this country from undergoing the same increase in HIV prevalence observed in its neighbors, immediate intervention measures and sufficient epidemiological research are urgently needed.
Phylogeography of Highly Pathogenic H5 Avian Influenza Viruses in China
Xiaowen Li, Xueying Li, Bing Xu
2020, 35(5): 548-555.  doi: 10.1007/s12250-020-00193-7
Received: 26 May 2019 Accepted: 17 December 2020 Published: 08 May 2020
HTML Full Text [PDF 1838KB] Springerlink ESM
The spread of H5 highly pathogenic avian influenza viruses poses serious threats to the poultry industry, wild bird ecology and human health. Circulation of H5 viruses between poultry and wild birds is a significant public health threat in China. Thus, viral migration networks in this region need to be urgently studied. Here, we conducted molecular genetic analyses of the hemagglutinin genes of H5 highly pathogenic avian influenza viruses in multiple hosts from 2000 to 2018 in China. Our aim was to clarify the roles of different hosts in the evolution of H5 viruses. We used a flexible Bayesian statistical framework to simulate viral space diffusion and continuous-time Markov chains to infer the dynamic evolutionary process of spatiotemporal dissemination. Bayesian phylogeographic analysis of H5 viruses showed for the first time that H5 viruses in poultry and wild birds were present in Guangdong Province. Furthermore, Guangdong, Jiangsu, Shanghai and Hunan acted as the epicenters for the spread of various H5 subtypes viruses in poultry, and Henan, Shanghai, Hong Kong and Inner Mongolia acted as epicenters for the spread of various H5 subtypes viruses in wild birds. Thus, H5 viruses exhibited distinct evolutionary dynamics in poultry and wild birds. Our findings extend our understanding of the transmission and spread of highly pathogenic H5 avian influenza viruses in China.
Molecular Epidemiology and Vaccine Compatibility Analysis of Seasonal Influenza Viruses in Wuhan, 2016–2019
Liang-Jun Chen, Jing-Jing Guo, Wei-Wei Guo, E-Xiang Shen, Xin Wang, Kai-Ji Li, Jie Yan, Mang Shi, Yi-Rong Li, Wei Hou
2020, 35(5): 556-565.  doi: 10.1007/s12250-020-00225-2
Received: 15 December 2019 Accepted: 07 March 2020 Published: 11 May 2020
HTML Full Text [PDF 510KB] Springerlink ESM
Influenza viruses (FLUV) cause high morbidity and mortality annually in the world and pose a serious threat to the public health. Wuhan, as an important transportation hub in China, has a dense population and suitable climate, which also lays a major hidden danger for the outbreak of influenza. To survey and characterize the seasonal FLUV in Wuhan during 2016–2019, we collected 44, 738 throat swabs, among which 15.5% were influenza A (FLUAV) positive, 6.1% influenza B (FLUBV) and 0.3% co-infection. By monitoring FLUV in each month from June 2016 to May 2019, different with the previously seasonality pattern, only a single influenza peak was appeared in winter of 2017–2018 and 2018–2019, respectively. These data indicated that the complex circulation pattern of seasonal influenza in Wuhan. In addition, we found the age group was skewed towards 5–14 years group whose activity were mostly school based, which suggested school may be an important place for influenza outbreaks. Meanwhile, phylogenic analysis revealed that two subtypes (subclade 3C.2a2 and 3C.2a1b) of A(H3N2) were circulating in Wuhan and there was an obvious transition in 2018 because the two subclades were detected simultaneously. Furthermore, by estimating the vaccine effectiveness, we found that the vaccine strain of FLUAV didn't seem to match very well the current epidemic strain, especially A(H3N2). Hence, more accurate prediction of seasonal outbreak is essential for vaccine design. Taken together, our results provided the current information about seasonal FLUV in Wuhan which form the basis for vaccine updating.
Effect of Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 Alpha Variants on Spontaneous Clearance and Fibrosis Progression during Hepatitis C Virus Infection in Moroccan Patients
Raouia ElFihry, Mohcine Elmessaoudi-Idrissi, Fatima-Zahra Jadid, Imane Zaidane, Hajar Chihab, Mohamed Tahiri, Mostafa Kabine, Wafaa Badre, Isabelle Chemin, Agnes Marchio, Pascal Pineau, Sayeh Ezzikouri, Soumaya Benjelloun
2020, 35(5): 566-574.  doi: 10.1007/s12250-020-00220-7
Received: 04 October 2019 Accepted: 08 February 2020 Published: 15 April 2020
HTML Full Text [PDF 440KB] Springerlink
Hepatitis C virus (HCV) is still one of the main causes of liver disease worldwide. Metabolic disorders, including non-alcoholic fatty liver disease (NAFLD), induced by HCV have been shown to accelerate the progression of fibrosis to cirrhosis and to increase the risk of hepatocellular carcinoma. An optimal peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) activity is crucial to prevent NAFLD installation. The present study aims to investigate the associations between two common PPARGC1A polymorphisms (rs8192678 and rs12640088) and the outcomes of HCV infection in a North African context. A series of 592 consecutive Moroccan subjects, including 292 patients with chronic hepatitis C (CHC), 100 resolvers and 200 healthy controls were genotyped using a TaqMan allelic discrimination assay. PPARGC1A variations at rs8192678 and rs12640088 were not associated with spontaneous clearance of HCV infection (adjusted ORs = 0.76 and 0.79 respectively, P > 0.05, for both). Furthermore, multivariable logistic regression analysis showed that both SNPs were not associated with fibrosis progression (OR = 0.71; 95% CI 0.20–2.49; P = 0.739; OR = 1.28; 95% CI 0.25–6.54; P = 0.512, respectively). We conclude that, in the genetic context of South Mediterranean patients, rs8192678 and rs12640088 polymorphisms of PPARGC1A are neither associated with spontaneous clearance nor with disease progression in individuals infected with HCV.
Cutaneous Dengue Virus Inoculation Triggers Strong B Cell Reactions but Contrastingly Poor T Cell Responses
Edith Marcial-Juárez, Julio García-Cordero, Raúl Antonio Maqueda-Alfaro, Rafael Eduardo Saucedo-López, Luvia Enid Sánchez-Torres, Leticia Cedillo-Barrón, Leopoldo Flores-Romo
2020, 35(5): 575-587.  doi: 10.1007/s12250-020-00213-6
Received: 16 October 2019 Accepted: 24 December 2019 Published: 20 April 2020
HTML Full Text [PDF 8283KB] Springerlink
Dengue is a global health problem without current specific treatment nor safe vaccines available. While severe dengue is related to pre-existing non-neutralizing dengue virus (DENV) antibodies, the role of T cells in protection or pathology is unclear. Using cutaneous DENV infection in immunocompetent mice we previously showed the generation of PNA+ germinal centers (GCs), now we assessed the activation and proliferation of B and T cells in draining lymph nodes (DLNs). We found a drastic remodelling of DLN compartments from 7 to 14 days post-infection (dpi) with greatly enlarged B cell follicles, occupying almost half of the DLN area compared to ~24% in naïve conditions. Enormous clusters of proliferating (Ki-67+) cells inside B follicles were found 14 dpi, representing ~33% of B cells in DLNs but only ~2% in non-infected mice. Inside GCs, we noticed an important recruitment of tingle body macrophages removing apoptotic cells. In contrast, the percentage of paracortex area and total T cells decreased by 14–16 dpi, compared to controls. Scattered randomly distributed Ki-67+ T cells were found, similar to non-infected mice. CD69 expression by CD4+ and CD8+ T cells was minor, while it was remarkable in B cells, representing 1764.7% of change from basal levels 3 dpi. The apparent lack of T cell responses cannot be attributed to apoptosis since no significant differences were observed compared to non-infected mice. This study shows massive B cell activation and proliferation in DLNs upon DENV infection. In contrast, we found very poor, almost absent CD4+ and CD8+ T cell responses.
Depletion but Activation of CD56dimCD16+ NK Cells in Acute Infection with Severe Fever with Thrombocytopenia Syndrome Virus
Mengmeng Li, Yan Xiong, Mingyue Li, Wenjing Zhang, Jia Liu, Yanfang Zhang, Shue Xiong, Congcong Zou, Boyun Liang, Mengji Lu, Dongliang Yang, Cheng Peng, Xin Zheng
2020, 35(5): 588-598.  doi: 10.1007/s12250-020-00224-3
Received: 11 August 2019 Accepted: 28 February 2020 Published: 19 May 2020
HTML Full Text [PDF 1556KB] Springerlink ESM
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality (12%–30%). The mechanism by which the SFTS bunyavirus (SFTSV) causes severe illness remains unclear. To evaluate the phenotypic and functional characteristics of the NK cell subsets in SFTS patients, twenty-nine SFTS patients were sequentially sampled from admission until recovery. Phenotypic and functional characteristics of NK cell subsets in circulating blood were analysed via flow cytometry. Then, correlations between NK cell subset frequencies and the SFTS index (SFTSI) were evaluated in all SFTS patients (15 mild, 14 severe) upon admission. The frequencies of CD56dimCD16+ NK cells were greatly decreased in early SFTSV infection and were negatively correlated with disease severity. Additionally, higher Ki-67 and granzyme B expression and relatively lower NKG2A expression in CD56dimCD16+ NK cells were observed in acute infection. Moreover, the effector function of CD56dim NK cells was increased in the acute phase compared with the recovery phase in nine severe SFTS patients. Additionally, interleukin (IL)-15, interferon (IFN)-α, IL-18 and IFN-γ secretion was markedly increased during early infection. Collectively, despite depletion of CD56dimCD16+ NK cells, activation and functional enhancement of CD56dimCD16+ NK cells were still observed, suggesting their involvement in defence against early SFTSV infection.
Myristoylation of EV71 VP4 is Essential for Infectivity and Interaction with Membrane Structure
Jiaming Cao, Meng Qu, Hongtao Liu, Xuan Wan, Fang Li, Ali Hou, Yan Zhou, Bo Sun, Linjun Cai, Weiheng Su, Chunlai Jiang
2020, 35(5): 599-613.  doi: 10.1007/s12250-020-00226-1
Received: 12 December 2019 Accepted: 03 March 2020 Published: 12 May 2020
HTML Full Text [PDF 2572KB] Springerlink ESM
The Enterovirus 71 (EV71) VP4 is co-translationally linked to myristic acid at its amino-terminal glycine residue. However, the role of this myristoylation in the EV71 life cycle remains largely unknown. To investigate this issue, we developed a myristoylation-deficient virus and reporter (luciferase) pseudovirus with a Gly-to-Ala mutation (G2A) on EV71 VP4. When transfecting the EV71-G2A genome encoding plasmid in cells, the loss of myristoylation on VP4 did not affect the expression of viral proteins and the virus morphology, however, it did significantly influence viral infectivity. Further, in myristoylation-deficient reporter pseudovirus-infected cells, the luciferase activity and viral genome RNA decreased significantly as compared to that of wild type virus; however, cytopathic effect and viral capsid proteins were not detected in myristoylation-deficient virus-infected cells. Also, although myristoylation-deficient viral RNA and proteins were detected in the second blind passage of infection, they were much fewer in number compared to that of the wild type virus. The replication of genomic RNA and negative-strand viral RNA were both blocked in myristoylation-deficient viruses, suggesting that myristoylation affects viral genome RNA release from capsid to cytoplasm. Besides, loss of myristoylation on VP4 altered the distribution of VP4-green fluorescent protein protein, which disappeared from the membrane structure fraction. Finally, a liposome leakage assay showed that EV71 myristoylation mediates the permeability of the model membrane. Hence, the amino-terminal myristoylation of VP4 is pivotal to EV71 infection and capsid-membrane structure interaction. This study provides novel molecular mechanisms regarding EV71 infection and potential molecular targets for antiviral drug design.
IP10, KC and M-CSF Are Remarkably Increased in the Brains from the Various Strains of Experimental Mice Infected with Different Scrapie Agents
Jia Chen, Cao Chen, Chao Hu, Lian Liu, Ying Xia, Lin Wang, Wei Yang, Hai-Yan Wu, Wei Zhou, Kang Xiao, Qi Shi, Yuezhang Wu, Zhi-Bao Chen, Xiao-Ping Dong
2020, 35(5): 614-625.  doi: 10.1007/s12250-020-00216-3
Received: 17 September 2019 Accepted: 27 November 2019 Published: 20 April 2020
HTML Full Text [PDF 1717KB] Springerlink
Activation of inflammatory cells and upregulations of a number of cytokines in the central nervous system (CNS) of patients with prion diseases are frequently observed. To evaluate the potential changes of some brain cytokines that were rarely addressed during prion infection, the levels of 17 different cytokines in the brain homogenates of mice infected with different scrapie mouse-adapted agents were firstly screened with Luminex assay. Significant upregulations of interferon gamma-induced protein 10 (IP10), keratinocyte chemoattractant (KC) and macrophage colony stimulating factor (M-CSF) were frequently detected in the brain lysates of many strains of scrapie infected mice. The upregulations of those three cytokines in the brains of scrapie infected mice were further validated by the individual specific ELISA and immunohistochemical assay. Increased specific mRNAs of IP10, M-CSF and KC in the brains of scrapie infected mice were also detected by the individual specific qRT-PCRs and IP10-specific digital PCR. Dynamic analyses of the brain samples collected at different time points post infection revealed the time-dependent increases of those three cytokines, particularly IP10 during the incubation period of scrapie infection. In addition, we also found that the levels of IP10 in cerebral spinal fluid (CSF) of 45 sporadic Creutzfeldt–Jakob disease (sCJD) patients were slightly but significantly higher than those of the cases who were excluded the diagnosis of prion diseases. These data give us a better understanding of inflammatory reaction during prion infection and progression of prion disease.
Establishment of Murine Infection Models with Biological Clones of Dengue Viruses Derived from a Single Clinical Viral Isolate
Zhihang Zheng, Min Li, Zhihua Liu, Xia Jin, Jin Sun
2020, 35(5): 626-636.  doi: 10.1007/s12250-020-00229-y
Received: 09 November 2019 Accepted: 11 March 2020 Published: 25 May 2020
HTML Full Text [PDF 2005KB] Springerlink
Dengue virus (DENV) is a single-stranded RNA virus transmitted by mosquitoes in tropical and subtropical regions. It causes dengue fever, dengue hemorrhagic fever and dengue shock syndrome in patients. Each year, 390 million people are estimated to be infected by four serotypes of dengue virus, creating a great burden on global public health and local economy. So far, no antiviral drug is available for dengue disease, and the newly licensed vaccine is far from satisfactory. One large obstacle for dengue vaccine and drug development is the lack of suitable small animal models. Although some DENV infection models have been developed, only a small number of viral strains can infect immunodeficient mice. In this study, with biologically cloned viruses from a single clinical isolate, we have established two mouse models of DENV infection, one is severe lethal infection in immunocompromised mice, and the other resembles self-limited disease manifestations in Balb/c mice with transient blockage of type Ⅰ IFN responses. This study not only offers new small animal models of dengue viral infection, but also provides new viral variants for further investigations on dengue viral pathogenesis.
Baculovirus Surface Display of Zika Virus Envelope Protein Protects against Virus Challenge in Mouse Model
Dan Luo, Yuanjiu Miao, Xianliang Ke, Zhongyuan Tan, Chun Hu, Penghui Li, Ting Wang, Yuan Zhang, Jianhong Sun, Yan Liu, Hanzhong Wang, Zhenhua Zheng
2020, 35(5): 637-650.  doi: 10.1007/s12250-020-00238-x
Received: 24 October 2019 Accepted: 10 April 2020 Published: 29 May 2020
HTML Full Text [PDF 5282KB] Springerlink ESM
Zika virus (ZIKV) is emerging as a significant pathogen worldwide and may cause severe neurological disorders such as fetal microcephaly and Guillain-Barre syndrome. No drug or listed vaccines are currently available for preventing ZIKV infection. As a major target of neutralizing, ZIKV envelop (E) protein usually used for vaccine development. Nevertheless, the immunogenicity of ZIKV envelop (E) protein expressed by baculovirus display system has never been assessed. In this study, we reported a new strategy for surface display of ZIKV E protein by a recombinant baculovirus vector derived from Autographa californica multiple nuclear polyhedrosis virus (AcMNPV) and assessed its immunogenicity in mice. We produced recombinant fusion ZIKV E protein linked with signal peptide (SP) and transmembrane domain (TM) of AcMNPV GP64. The results showed that the recombinant protein was easy to produce by baculovirus display system. BALB/c mice immunized with this recombinant E protein developed ZIKV specific serum antibodies. The anti-E protein sera from the mice were able to effectively neutralize ZIKV in vitro. More importantly, AG6 (IFN-α/β and IFN-γ receptor deficient) mice immunized with recombinant E protein were protected against lethal ZIKV challenge. Together, these findings demonstrated that the recombinant E protein displayed by baculovirus can be conveniently prepared and displayed good immunogenicity in immunized mice. It is a promising practical approach for prompting the development of vaccine and related immunology research.
Recombination of T4-like Phages and Its Activity against Pathogenic Escherichia coli in Planktonic and Biofilm Forms
Min Li, Donglin Shi, Yanxiu Li, Yuyi Xiao, Mianmian Chen, Liang Chen, Hong Du, Wei Zhang
2020, 35(5): 651-661.  doi: 10.1007/s12250-020-00233-2
Received: 09 October 2019 Accepted: 10 March 2020 Published: 25 May 2020
HTML Full Text [PDF 1647KB] Springerlink ESM
The increasing emergence of multi-drug resistant Escherichia coli (E. coli) has become a global concern, primarily due to the limitation of antimicrobial treatment options. Phage therapy has been considered as a promising alternative for treating infections caused by multi-drug resistant E. coli. However, the application of phages as a promising antimicrobial agent is limited by their narrow host range and specificity. In this research, a recombinant T4-like phage, named WGqlae, has been obtained by changing the receptor specificity determinant region of gene 37, using a homologous recombination platform of T4-like phages established by our laboratory previously. The engineered phage WGqlae can lyse four additional hosts, comparing to its parental phages WG01 and QL01. WGqlae showed similar characteristics, including thermo and pH stability, optimal multiplicity of infection and one-step growth curve, to the donor phage QL01. In addition, sequencing results showed that gene 37 of recombinant phage WGqlae had genetically stable even after 20 generations. In planktonic test, phage WGqlae had significant antimicrobial effects on E. coli DE192 and DE205B. The optical density at 600 nm (OD600) of E. coli in phage WGqlae treating group was significantly lower than that of the control group (P < 0.01). Besides, phage WGqlae demonstrated an obvious inhibitory effect on the biofilm formation and the clearance of mature biofilms. Our study suggested that engineered phages may be promising candidates for future phage therapy applications against pathogenic E. coli in planktonic and biofilm forms.
Pan-Genomic Analysis of African Swine Fever Virus
Ziming Wang, Lijia Jia, Jing Li, Haizhou Liu, Di Liu
2020, 35(5): 662-665.  doi: 10.1007/s12250-019-00173-6
Received: 10 September 2019 Accepted: 17 October 2019 Published: 11 November 2019
HTML Full Text [PDF 647KB] Springerlink ESM
Development of an MCA-Based Real Time RT-qPCR Assay for the Simultaneous Detection and Differentiation of Duck Hepatitis A Virus Types 1 and 3
Chunchun Meng, Yunxiu Huang, Zaib Ur Rehman, Wen Hu, Chuanfeng Li, Ruiying Liang, Zongyan Chen, Kaijie Song, Tianchao Wei, Guangqing Liu
2020, 35(5): 666-669.  doi: 10.1007/s12250-020-00211-8
Received: 16 October 2019 Accepted: 03 March 2020 Published: 08 April 2020
HTML Full Text [PDF 683KB] Springerlink
Correction to: Establishment of Murine Infection Models with Biological Clones of Dengue Viruses Derived from A Single Clinical Viral Isolate
Zhihang Zheng, Min Li, Zhihua Liu, Xia Jin, Jin Sun
2020, 35(5): 670-671.  doi: 10.1007/s12250-020-00303-5
Published: 30 September 2020
HTML Full Text [PDF 465KB] Springerlink