2023 Vol.38(5)

Evolutionary conflicts between viruses and hosts compel them to ceaselessly develop novel offense or defense strategies. Type I interferons (IFN) initiate robust intracellular antiviral programmes, representing the classic innate immunity in mammals. Nevertheless, pathogenic hantaviruses, especially Hantaan viruses (HTNV), might resoundingly evade IFN responses at late infection stage, the underlying mechanism of which remains opaque. In this issue, Si et al. demonstrated that HTNV infection blocked JAK/STAT signaling by activating the receptor-interacting protein kinase 3 (RIPK3), but not triggering necroptosis. RIPK3 ablation efficiently promoted the expression of IFN-stimulated genes (ISG) and restricted viral replication in vitro. RIPK3 knockout mice also acquired prompt HTNV clearance ability with strengthened systemic inflammatory responses. Further investigation indicated that RIPK3 interfered with IFN pathway by binding to and incapacitating STAT1 during late HTNV infection stage. The cover image illustrates the possible immune evasion process of HTNV by manipulating RIPK3 traps to impede STAT1-mediate antiviral effects (kindly designed and provided by Hongwei Ma, Fanglin Zhang, and Yingfeng Lei). See page 741-754 for details.


Research Articles

Diversity and independent evolutionary profiling of rodent-borne viruses in Hainan, a tropical island of China

Youyou Li, Chuanning Tang, Yun Zhang, Zihan Li, Gaoyu Wang, Ruoyan Peng, Yi Huang, Xiaoyuan Hu, Henan Xin, Boxuan Feng, Xuefang Cao, Yongpeng He, Tonglei Guo, Yijun He, Haoxiang Su, Xiuji Cui, Lina Niu, Zhiqiang Wu, Jian Yang, Fan Yang, Gang Lu, Lei Gao, Qi Jin, Meifang Xiao, Feifei Yin, Jiang Du

2023, 38(5): 651 doi: 10.1016/j.virs.2023.08.003

Received: 21 March 2023 Accepted: 08 August 2023
Abstract [PDF 6643 KB] ScienceDirect ESM
The risk of emerging infectious diseases (EID) is increasing globally. More than 60% of EIDs worldwide are caused by animal-borne pathogens. This study aimed to characterize the virome, analyze the phylogenetic evolution, and determine the diversity of rodent-borne viruses in Hainan Province, China. We collected 682 anal and throat samples from rodents, combined them into 28 pools according to their species and location, and processed them for next-generation sequencing and bioinformatics analysis. The diverse viral contigs closely related to mammals were assigned to 22 viral families. Molecular clues of the important rodent-borne viruses were further identified by polymerase chain reaction for phylogenetic analysis and annotation of genetic characteristics such as arenavirus, coronavirus, astrovirus, pestivirus, parvovirus, and papillomavirus. We identified pestivirus and bocavirus in Leopoldoms edwardsi from Huangjinjiaoling, and bocavirus in Rattus andamanensis from the national nature reserves of Bangxi with low amino acid identity to known pathogens are proposed as the novel species, and their rodent hosts have not been previously reported to carry these viruses. These results expand our knowledge of viral classification and host range and suggest that there are highly diverse, undiscovered viruses that have evolved independently in their unique wildlife hosts in inaccessible areas.

Epizootiological surveillance of porcine circoviruses in free-ranging wild boars in China

Wenjie Gong, Haiying Du, Tong Wang, Heting Sun, Peng Peng, Siyuan Qin, Haidong Geng, Zheng Zeng, Wangwang Liang, Hongquan Ling, Changchun Tu, Zhongzhong Tu

2023, 38(5): 663 doi: 10.1016/j.virs.2023.08.008

Received: 18 April 2023 Accepted: 28 August 2023
Abstract [PDF 2183 KB] ScienceDirectESM
Four species of porcine circoviruses (PCV1-4) have been reported to circulate in Chinese domestic pigs, while the epizootiology of these viruses in free-ranging wild boars in China remains unknown. In this study, tissue and serum samples collected from diseased or apparently healthy wild boars between 2018 and 2020 in 19 regions of China were tested for the prevalence of PCV1-4 infections. Positive rates of PCV1, PCV2, and PCV3 DNA in the tissue samples of Chinese wild boars were 1.6% (4/247), 58.3% (144/247), and 10.9% (27/247) respectively, with none positive for PCV4. Sequence analysis of viral genome showed that the four PCV1 strains distributed in Hunan and Inner Mongolia shared 97.5%-99.6% sequence identity with global distributed reference strains. Comparison of the ORF2 gene sequences showed that 80 PCV2 strains widely distributed in 18 regions shared 79.5%-100% sequence identity with reference strains from domestic pigs and wild boars, and were grouped into PCV2a (7), PCV2b (31) and PCV2d (42). For PCV3, 17 sequenced strains shared 97.2%-100% nucleotide identity at the genomic level and could be divided into PCV3a (3), PCV3b (2) and PCV3c (12) based on the phylogeny of ORF2 gene sequences. Serological data revealed antibody positive rates against PCV1 and PCV2 of 11.4% (19/167) and 53.9% (90/167) respectively. The data obtained in this study improved our understanding about the epidemiological situations of PCVs infection in free-ranging wild boars in China and will be valuable for the prevention and control of diseases caused by PCVs infection.

Changing predominance of norovirus strains in children with acute gastroenteritis in Shanghai, 2018–2021

Lijuan Lu, Yuanyun Ao, Ran Jia, Huaqing Zhong, Pengcheng Liu, Menghua Xu, Liyun Su, Lingfeng Cao, Jin Xu

2023, 38(5): 671 doi: 10.1016/j.virs.2023.08.005

Received: 14 April 2023 Accepted: 17 August 2023
Abstract [PDF 2328 KB] ScienceDirectESM
Norovirus (NoV) is a major pathogen that causes acute gastroenteritis (AGE) in people of all ages, especially in children. In this study, we investigated the molecular epidemiological characteristics of NoV in children with AGE in Shanghai from 2018 to 2021. The overall detection rate of NoV was 11.9% (181/1545), with annual detection rates of 9.4% (36/381), 13.6% (29/213), 5.8% (13/226) and 14.2% (103/725), respectively. Of note, the prevalence of NoV in 2020 was significantly lower than that in 2018-2019 (10.9%, 65/594) (P=0.023) and 2021 (14.2%, 103/725) (P=0.000). The 181 NoV strains identified in this study were classified into the GI group (1.1%, 2/181), GII group (98.3%, 178/181) and GIX group (0.6%, 1/181) according to the VP1 gene. The most common NoV VP1 genotype was GII.4 Sydney_2012 (63.5%, 115/181), followed by GII.3 (19.9%, 36/181) and GII.2 (9.4%, 17/181). For P genotypes, 174 strains were sequenced successfully according to the RdRp gene, and the predominant genotype was GII.P16 (44.8%, 78/174), followed by GII.P31 (25.9%, 45/174) and GII.P12 (21.3%, 37/174). Among the 174 cases, GII.4 Sydney_2012[P16] (36.8%, 64/174) was the dominant genotype, followed by GII.4 Sydney_2012[P31] (25.3%, 44/174), GII.3[P12] (20.1%, 35/174) and GII.2[P16] (8.0%, 14/174). In particular, the dominant genotypes in Shanghai changed from GII.4 Sydney_2012[P31] in 2018-2019 to GII.4 Sydney_2012[P16] in 2020-2021. This is the first report to describe the epidemiological changes in NoV infection before and during the COVID-19 pandemic in Shanghai. These data highlight the importance of continuous surveillance for NoV in children with AGE in Shanghai.

HBV precore G1896A mutation promotes growth of hepatocellular carcinoma cells by activating ERK/MAPK pathway

Baoxin Zhao, Hongxiu Qiao, Yan Zhao, Zhiyun Gao, Weijie Wang, Yan Cui, Jian Li, Zhanjun Guo, Xia Chuai, Sandra Chiu

2023, 38(5): 680 doi: 10.1016/j.virs.2023.06.004

Received: 29 March 2023 Accepted: 14 June 2023
Abstract [PDF 3706 KB] ScienceDirectESM
Chronic hepatitis B virus (HBV) infection is one of the leading causes of hepatocellular carcinoma (HCC). The HBV genome is prone to mutate and several variants are closely related to the malignant transformation of liver disease. G1896A mutation (G to A mutation at nucleotide 1896) is one of the most frequently observed mutations in the precore region of HBV, which prevents HBeAg expression and is strongly associated with HCC. However, the mechanisms by which this mutation causes HCC are unclear. Here, we explored the function and molecular mechanisms of the G1896A mutation during HBV-associated HCC. G1896A mutation remarkably enhanced the HBV replication in vitro. Moreover, it increased tumor formation and inhibited apoptosis of hepatoma cells, and decreased the sensitivity of HCC to sorafenib. Mechanistically, the G1896A mutation could activate ERK/MAPK pathway to enhanced sorafenib resistance in HCC cells and augmented cell survival and growth. Collectively, our study demonstrates for the first time that the G1896A mutation has a dual regulatory role in exacerbating HCC severity and sheds some light on the treatment of G1896A mutation-associated HCC patients.

miR-204 suppresses porcine reproductive and respiratory syndrome virus (PRRSV) replication via inhibiting LC3B-mediated autophagy

Yao Yao, Sihan Li, Yingqi Zhu, Yangyang Xu, Siyuan Hao, Shuyuan Guo, Wen-Hai Feng

2023, 38(5): 690 doi: 10.1016/j.virs.2023.07.004

Received: 07 April 2023 Accepted: 07 July 2023
Abstract [PDF 1741 KB] ScienceDirectESM
Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV) has been regarded as a persistent challenge for the swine farms worldwide. microRNAs (miRNAs) play key roles in regulating almost every important biological process, including virus-host interaction. In this study, we found that miR-204 was highly expressed in cells that were not permissive to PRRSV infection compared with cells susceptible to PRRSV infection. Subsequently, we demonstrated that overexpression of miR-204 significantly inhibited PRRSV replication in porcine alveolar macrophages (PAMs). Through bioinformatic analysis, we found that there existed a potential binding site of miR-204 on the 3′UTR of microtubule associated protein 1 light chain 3B (MAP1LC3B, LC3B), a hallmark of autophagy. Applying experiments including luciferase reporter assay and UV cross-linking and immunoprecipitation (CLIP) assay, we demonstrated that miR-204 directly targeted LC3B, thereby downregulating autophagy. Meanwhile, we investigated the interplay between autophagy and PRRSV replication in PAMs, confirming that PRRSV infection induces autophagy, which in turn facilitates viral replication. Overall, we verify that miR-204 suppresses PRRSV replication via inhibiting LC3B-mediated autophagy in PAMs. These findings will provide a novel potential approach for us to develop antiviral therapeutic agents and controlling measures for future PRRSV outbreaks.

Long noncoding RNA 1392 regulates MDA5 by interaction with ELAVL1 to inhibit coxsackievirus B5 infection

Jing Li, Jinwei Li, Peiying Teng, Fan Yang, Jihong Zhang, Bo Sun, Wei Chen

2023, 38(5): 699 doi: 10.1016/j.virs.2023.08.001

Received: 25 August 2022 Accepted: 21 July 2023
Abstract [PDF 1843 KB] ScienceDirectESM
Long noncoding RNAs (lncRNAs) modulate many aspects of biological and pathological processes. Recent studies have shown that host lncRNAs participate in the antiviral immune response, but functional lncRNAs in coxsackievirus B5 (CVB5) infection remain unknown. Here, we identified a novel cytoplasmic lncRNA, LINC1392, which was highly inducible in CVB5 infected RD cells in a time- and dose-dependent manner, and also can be induced by the viral RNA and IFN-β. Further investigation showed that LINC1392 promoted several important interferon-stimulated genes (ISGs) expression, including IFIT1, IFIT2, and IFITM3 by activating MDA5, thereby inhibiting the replication of CVB5 in vitro. Mechanistically, LINC1392 bound to ELAV like RNA binding protein 1 (ELAVL1) and blocked ELAVL1 interaction with MDA5. Functional study revealed that the 245-835 nt locus of LINC1392 exerted the antiviral effect and was also an important site for ELAVL1 binding. In mice, LINC1392 could inhibit CVB5 replication and alleviated the histopathological lesions of intestinal and brain tissues induced by viral infection. Our findings collectively reveal that the novel LINC1392 acts as a positive regulator in the IFN-I signaling pathway against CVB5 infection. Elucidating the underlying mechanisms on how lncRNA regulats the host innate immunity response towards CVB5 infection will lay the foundation for antiviral drug research.

Autophagy induced by human adenovirus B7 structural protein VI inhibits viral replication

Linlin Zhang, Yali Duan, Wei Wang, Qi Li, Jiao Tian, Yun Zhu, Ran Wang, Zhengde Xie

2023, 38(5): 709 doi: 10.1016/j.virs.2023.08.002

Received: 09 February 2023 Accepted: 31 July 2023
Abstract [PDF 3976 KB] ScienceDirect ESM
Human adenovirus B7 (HAdV-B7) causes severe acute lower respiratory tract infections in children. However, neither the child-specific antivirals or vaccines are available, nor the pathogenesis is clear. Autophagy, as part of innate immunity, plays an important role in resistance to viral infection by degrading the virus and promoting the development of innate and adaptive immunity. This study provided evidence that HAdV-B7 infection induced complete autophagic flux, and the pharmacological induction of autophagy decreased HAdV-B7 replication. In this process, the host protein Bcl2-associated athanogene 3 (BAG3) mediated autophagy to inhibit the replication of HAdV-B7 by binding to the PPSY structural domain of viral protein pVI through its WW structural domain. These findings further our understanding of the host immune response during viral infection and will help to develop broad anti-HAdV therapies.

Inactivated SARS-CoV-2 booster vaccine enhanced immune responses in patients with chronic liver diseases

Yongmei Liu, Jianhua Lu, Haoting Zhan, Wenfang Yuan, Xiaomeng Li, Haiyan Kang, Haolong Li, Yongliang Chen, Linlin Cheng, Xingli Sun, Haojie Zheng, Wei Wang, Erhei Dai, Yongzhe Li

2023, 38(5): 723 doi: 10.1016/j.virs.2023.07.005

Received: 20 April 2023 Accepted: 19 July 2023
Abstract [PDF 2080 KB] ScienceDirectESM
Chronic liver disease (CLD) entails elevated risk of COVID-19 severity and mortality. The effectiveness of the booster dose of inactivated SARS-CoV-2 vaccine in stimulating antibody response in CLD patients is unclear. Therefore, we conducted a cross-sectional study involving 237 adult CLD patients and 170 healthy controls (HC) to analyze neutralizing antibodies (NAbs) against SARS-CoV-2 prototype and BA.4/5 variant, anti-receptor binding domain (RBD) IgG, and total anti-SARS-CoV-2 antibodies. Serum levels of the total anti-SARS-CoV-2 antibodies, anti-RBD IgG and inhibition efficacy of NAbs were significantly elevated in CLD patients after the booster dose compared with the pre-booster dose, but were relatively lower than those of HCs. Induced humoral responses decreased over time after booster vaccination. The neutralization efficiency of the serum against BA.4/5 increased but remained below the inhibition threshold. All four SARS-CoV-2 antibodies, including total anti-SARS-CoV-2 antibodies, anti-RBD IgG and NAbs against prototype and BA.4/5, were lower in patients with severe CLD than those with non-severe CLD. After booster shot, age and time after the last vaccine were the risk factors for seropositivity of NAb against BA.4/5 in CLD patients. Additionally, white blood cell counts and hepatitis B core antibodies were the protective factors, and severe liver disease was the risk factor associated with seropositivity of total anti-SARS-CoV-2 antibodies. Overall, our data uncovered that antibody responses were improved in CLD patients and peaked at 120 days after the booster vaccines. All antibodies excepting total anti-SARS-CoV-2 antibodies declined after peak. CLD patients exhibited impaired immunologic responses to vaccination and weakened NAbs against BA.4/5, which hindered the protective effect of the booster shot against Omicron prevalence. Cellular immune responses should be further evaluated to determine the optimal vaccine regimen for CLD patients.

Abnormal liver function in children hospitalized with acute respiratory infection of adenoviruses: a retrospective study

Xingui Tian, Xiao Li, Shuyan Qiu, Rong Zhou, Wenkuan Liu

2023, 38(5): 735 doi: 10.1016/j.virs.2023.07.007

Received: 20 April 2023 Accepted: 27 July 2023
Abstract [PDF 815 KB] ScienceDirectESM
Human adenoviruses (HAdVs) can cause acute hepatitis in immunocompromised patients. However, it is unclear whether HAdVs are contributors to hepatitis in immunocompetent children. In this study, the liver function test (LFT) results were retrospectively analyzed among children hospitalized (age <14 years) between January 2016 and October 2019 for acute respiratory infection caused by adenoviruses. Alanine transaminase (ALT) and aspartate aminotransferase (AST) levels were elevated in 7.74% and 46.89% of patients, respectively. All patients with >2 folds of the upper limit of ALT or AST levels were infected with HAdV-7 or HAdV-55. Significantly higher levels of ALT, AST, γ-glutamyl transpeptidase (γ-GT), and lower albumin levels were observed in the HAdV-7 infection group than in the HAdV-3 infection group. HAdV-55 infection led to significantly higher γ-GT, total bilirubin, and direct bilirubin levels than the other infection types. The records of four patients with serial monitoring of the LFT results were further analyzed. Multiple indicators remained abnormal during the entire hospitalization in these patients. These results indicate that HAdV infection is often accompanied by abnormal liver function, and HAdV-7 and HAdV-55 might be under-recognized contributors to hepatitis among children.

RIPK3 promotes hantaviral replication by restricting JAK-STAT signaling without triggering necroptosis

Yue Si, Haijun Zhang, Ziqing Zhou, Xudong Zhu, Yongheng Yang, He Liu, Liang Zhang, Linfeng Cheng, Kerong Wang, Wei Ye, Xin Lv, Xijing Zhang, Wugang Hou, Gang Zhao, Yingfeng Lei, Fanglin Zhang, Hongwei Ma

2023, 38(5): 741 doi: 10.1016/j.virs.2023.08.006

Received: 22 February 2023 Accepted: 21 August 2023
Abstract [PDF 5449 KB] ScienceDirectESM
Hantaan virus (HTNV) is a rodent-borne virus that causes hemorrhagic fever with renal syndrome (HFRS), resulting in a high mortality rate of 15%. Interferons (IFNs) play a critical role in the anti-hantaviral immune response, and IFN pretreatment efficiently restricts HTNV infection by triggering the expression of a series of IFN-stimulated genes (ISGs) through the Janus kinase-signal transducer and activator of transcription 1 (JAK-STAT) pathway. However, the tremendous amount of IFNs produced during late infection could not restrain HTNV replication, and the mechanism remains unclear. Here, we demonstrated that receptor-interacting protein kinase 3 (RIPK3), a crucial molecule that mediates necroptosis, was activated by HTNV and contributed to hantavirus evasion of IFN responses by inhibiting STAT1 phosphorylation. RNA-seq analysis revealed the upregulation of multiple cell death-related genes after HTNV infection, with RIPK3 identified as a key modulator of viral replication. RIPK3 ablation significantly enhanced ISGs expression and restrained HTNV replication, without affecting the expression of pattern recognition receptors (PRRs) or the production of type I IFNs. Conversely, exogenously expressed RIPK3 compromised the host's antiviral response and facilitated HTNV replication. RIPK3-/- mice also maintained a robust ability to clear HTNV with enhanced innate immune responses. Mechanistically, we found that RIPK3 could bind STAT1 and inhibit STAT1 phosphorylation dependent on the protein kinase domain (PKD) of RIPK3 but not its kinase activity. Overall, these observations demonstrated a noncanonical function of RIPK3 during viral infection and have elucidated a novel host innate immunity evasion strategy utilized by HTNV.

Enterovirus D68 infection upregulates SOCS3 expression to inhibit JAK-STAT3 signaling and antagonize the innate interferon response of the host

Yuling Zhang, Leling Xu, Zhe Zhang, Xin Su, Zhiyun Wang, Tao Wang

2023, 38(5): 755 doi: 10.1016/j.virs.2023.08.007

Received: 09 March 2023 Accepted: 25 August 2023
Abstract [PDF 4628 KB] ScienceDirectESM
Enterovirus D68 (EV-D68) can cause respiratory diseases and acute flaccid paralysis, posing a great threat to public health. Interferons are cytokines secreted by host cells that have broad-spectrum antiviral effects, inducing the expression of hundreds of interferon-stimulated genes (ISGs). EV-D68 activates ISG expression early in infection, but at a later stage, the virus suppresses ISG expression, a strategy evolved by EV-D68 to antagonize interferons. Here, we explore a host protein, suppressor of cytokine signaling 3 (SOCS3), is upregulated during EV-D68 infection and antagonizes the antiviral effects of type I interferon. We subsequently demonstrate that the structural protein of EV-D68 upregulated the expression of RFX7, a transcriptional regulator of SOCS3, leading to the upregulation of SOCS3 expression. Further exploration revealed that SOCS3 plays its role by inhibiting the phosphorylation of signal transducer and activator of transcription 3 (STAT3). The expression of SOCS3 inhibited the expression of ISG, thereby inhibiting the antiviral effect of type I interferon and promoting EV-D68 transcription, protein production, and viral titer. Notably, a truncated SOCS3, generated by deleting the kinase inhibitory region (KIR) domain, failed to promote replication and translation of EV-D68. Based on the above studies, we designed a short peptide named SOCS3 inhibitor, which can specifically bind and inhibit the KIR structural domain of SOCS3, significantly reducing the RNA and protein levels of EV-D68. In summary, our results demonstrated a novel mechanism by which EV-D68 inhibits ISG transcription and antagonizes the antiviral responses of host type I interferon.

Development of a novel virus-like particle-based vaccine for preventing tick-borne encephalitis virus infection

Jielin Tang, Muqing Fu, Chonghui Xu, Bao Xue, Anqi Zhou, Sijie Chen, He Zhao, Yuan Zhou, Jizheng Chen, Qi Yang, Xinwen Chen

2023, 38(5): 767 doi: 10.1016/j.virs.2023.06.003

Received: 12 March 2023 Accepted: 12 June 2023
Abstract [PDF 2218 KB] ScienceDirectESM
Tick-borne encephalitis virus (TBEV) is an important tick-borne pathogen that poses as a serious public health concern. The coverage and immunogenicity of the currently available vaccines against TBEV are relatively low; therefore, it is crucial to develop novel and effective vaccines against TBEV. The present study describes a novel strategy for the assembly of virus-like particles (VLPs) by co-expressing the structural (core/prM/E) and non-structural (NS2B/NS3Pro) proteins of TBEV. The efficacy of the VLPs was subsequently evaluated in C57BL/6 mice, and the resultant IgG serum could neutralize both Far-Eastern and European subtypes of TBEV. These findings indicated that the VLP-based vaccine elicited the production of cross-subtype reactive antibodies. The VLPs provided protection to mice lacking the type I interferon receptor (IFNAR) against lethal TBEV challenge, with undetectable viral load in brain and intestinal tissues. Furthermore, the group that received the VLP vaccine did not exhibit significant pathological changes and the inflammatory factors were significantly suppressed compared to the control group. Immunization with the VLP vaccine induced the production of multiple-cytokine-producing antiviral CD4+ T cells in vivo, including TNF-α+, IL-2+, and IFN-γ+ T cells. Altogether, the findings suggest that noninfectious VLPs can serve as a potentially safe and effective vaccine candidate against diverse subtypes of TBEV.

Identification of a receptor tyrosine kinase inhibitor CP-724714 inhibits SADS-CoV related swine diarrhea coronaviruses infection in vitro

Ling Zhou, Cheng Li, Ruiyu Zhang, Qianniu Li, Yuan Sun, Yaoyu Feng, Tian Lan, Jingyun Ma

2023, 38(5): 778 doi: 10.1016/j.virs.2023.06.010

Received: 11 January 2023 Accepted: 29 June 2023
Abstract [PDF 4873 KB] ScienceDirectESM
The outbreak of the COVID-19 epidemic in 2020 has caused unprecedented panic among all mankind, pointing the major importance of effective treatment. Since the emergence of the swine acute diarrhea syndrome coronavirus (SADS-CoV) at the end of 2017, multiple reports have indicated that the bat-related SADS-CoV possesses a potential threat for cross-species transmission. Vaccines and antiviral drugs development deserve more attention. In this study, we found that the HER2 phosphorylation inhibitor (CP-724714) inhibited SADS-CoV infection in a dose-dependent manner. Further validation demonstrated that CP-724714 affected at the post-entry stage of SADS-CoV infection cycle. Also, efficient SADS-CoV infection required the activation of HER2 and its cascade Ras-Raf-Mek-Erk signaling pathway. In addition, CP-724714 has a broad-spectrum anti-swine diarrhea coronaviruses activity, and can dose-dependently combat SADS-CoV, porcine epidemic diarrhea virus (PEDV), porcine deltacoronavirus (PDCoV) and transmissible gastroenteritis virus (TGEV) infection in vitro with a specificity index of greater than 21.98, 9.38, 95.23 and 31.62, respectively. These results highlight the potential utility of CP-724714 or antiviral drugs targeting with HER2 and its cascade Ras-Raf-Mek-Erk signaling pathway as host-targeted SADS-CoV and other related coronaviruses therapeutics.

Nanobodies with cross-neutralizing activity provide prominent therapeutic efficacy in mild and severe COVID-19 rodent models

Qiuxue Han, Shen Wang, Zhenshan Wang, Cheng Zhang, Xinyue Wang, Na Feng, Tiecheng Wang, Yongkun Zhao, Hang Chi, Feihu Yan, Xianzhu Xia

2023, 38(5): 787 doi: 10.1016/j.virs.2023.07.003

Received: 16 March 2023 Accepted: 04 July 2023
Abstract [PDF 5515 KB] ScienceDirect
The weakened protective efficacy of COVID-19 vaccines and antibodies caused by SARS-CoV-2 variants presents a global health emergency, which underscores the urgent need for universal therapeutic antibody intervention for clinical patients. Here, we screened three alpacas-derived nanobodies (Nbs) with neutralizing activity from twenty RBD-specific Nbs. The three Nbs were fused with the Fc domain of human IgG, namely aVHH-11-Fc, aVHH-13-Fc and aVHH-14-Fc, which could specifically bind RBD protein and competitively inhibit the binding of ACE2 receptor to RBD. They effectively neutralized SARS-CoV-2 pseudoviruses D614G, Alpha, Beta, Gamma, Delta, and Omicron sub-lineages BA.1, BA.2, BA.4, and BA.5 and authentic SARS-CoV-2 prototype, Delta, and Omicron BA.1, BA.2 strains. In mice-adapted COVID-19 severe model, intranasal administration of aVHH-11-Fc, aVHH-13-Fc and aVHH-14-Fc effectively protected mice from lethal challenges and reduced viral loads in both the upper and lower respiratory tracts. In the COVID-19 mild model, aVHH-13-Fc, which represents the optimal neutralizing activity among the above three Nbs, effectively protected hamsters from the challenge of SARS-CoV-2 prototype, Delta, Omicron BA.1 and BA.2 by significantly reducing viral replication and pathological alterations in the lungs. In structural modeling of aVHH-13 and RBD, aVHH-13 binds to the receptor-binding motif region of RBD and interacts with some highly conserved epitopes. Taken together, our study illustrated that alpaca-derived Nbs offered a therapeutic countermeasure against SARS-CoV-2, including those Delta and Omicron variants which have evolved into global pandemic strains.

Characterization of bacteriophage BUCT631 lytic for K1 Klebsiella pneumoniae and its therapeutic efficacy in Galleria mellonella larvae

Pengjun Han, Mingfang Pu, Yahao Li, Huahao Fan, Yigang Tong

2023, 38(5): 801 doi: 10.1016/j.virs.2023.07.002

Received: 09 April 2023 Accepted: 03 July 2023
Abstract [PDF 2504 KB] ScienceDirectESM
Severe infections caused by multidrug-resistant Klebsiella pneumoniae (K. pneumoniae) highlight the need for new therapeutics with activity against this pathogen. Phage therapy is an alternative treatment approach for multidrug-resistant K. pneumoniae infections. Here, we report a novel bacteriophage (phage) BUCT631 that can specifically lyse capsule-type K1 K. pneumoniae. Physiological characterization revealed that phage BUCT631 could rapidly adsorb to the surface of K. pneumoniae and form an obvious halo ring, and it had relatively favorable thermal stability (4-50 °C) and pH tolerance (pH=4-12). In addition, the optimal multiplicity of infection (MOI) of phage BUCT631 was 0.01, and the burst size was approximately 303 PFU/cell. Genomic analysis showed that phage BUCT631 has double-stranded DNA (total length of 44,812 bp) with a G + C content of 54.1%, and the genome contains 57 open reading frames (ORFs) and no virulence or antibiotic resistance related genes. Based on phylogenetic analysis, phage BUCT631 could be assigned to a new species in the genus Drulisvirus of the subfamily Slopekvirinae. In addition, phage BUCT631 could quickly inhibit the growth of K. pneumoniae within 2 h in vitro and significantly elevated the survival rate of K. pneumoniae infected Galleria mellonella larvae from 10% to 90% in vivo. These studies suggest that phage BUCT631 has promising potential for development as a safe alternative for control and treatment of multidrug-resistant K. pneumoniae infection.

Genomic similarity and antibody-dependent enhancement of immune serum potentially affect the protective efficacy of commercial MLV vaccines against NADC30-like PRRSV

Yang Li, Lele Xu, Dian Jiao, Zifang Zheng, Zhihao Chen, Yang Jing, Zhiwei Li, Zhiqian Ma, Yingtong Feng, Xuyang Guo, Yumiao Wang, Yuan He, Haixue Zheng, Shuqi Xiao

2023, 38(5): 813 doi: 10.1016/j.virs.2023.08.010

Received: 04 January 2023 Accepted: 28 August 2023
Abstract [PDF 5142 KB] ScienceDirectESM
Porcine reproductive and respiratory syndrome (PRRS) is one of the most significant diseases affecting the pig industry worldwide. The PRRSV mutation rate is the highest among the RNA viruses. To date, NADC30-like PRRSV and highly pathogenic PRRSV (HP-PRRSV) are the dominant epidemic strains in China; however, commercial vaccines do not always provide sufficient cross-protection, and the reasons for insufficient protection are unclear. This study isolated a wild-type NADC30-like PRRSV, SX-YL1806, from Shaanxi Province. Vaccination challenge experiments in piglets showed that commercial modified live virus (MLV) vaccines provided good protection against HP-PRRSV. However, it could not provide sufficient protection against the novel strain SX-YL1806. To explore the reasons for this phenomenon, we compared the genomic homology between the MLV strain and HP-PRRSV or NADC30-like PRRSV and found that the MLV strain had a lower genome similarity with NADC30-like PRRSV. Serum neutralization assay showed that MLV-immune serum slightly promoted the homologous HP-PRRSV replication and significantly promoted the heterologous NADC30-like PRRSV strain replication in vitro, suggesting that antibody-dependent enhancement (ADE) might also play a role in decreasing MLV protective efficacy. These findings expand our understanding of the potential factors affecting the protective effect of PRRSV MLV vaccines against the NADC30-like strains.

Comparative study of the pathogenicity of the mosquito origin strain and duck origin strain of Tembusu virus in ducklings and three-week-old mice

Xiaoli Wang, Yu He, Jiaqi Guo, Zhen Wu, Andres Merits, Mingshu Wang, Renyong Jia, Dekang Zhu, Mafeng Liu, Xinxin Zhao, Qiao Yang, Ying Wu, Shaqiu Zhang, Juan Huang, Xumin Ou, Qun Gao, Di Sun, Anchun Cheng, Shun Chen

2023, 38(5): 827 doi: 10.1016/j.virs.2023.07.006

Received: 24 April 2023 Accepted: 26 July 2023
Abstract [PDF 2971 KB] ScienceDirectESM
Highlights:1. TMUV can infect Kunming mice by intracranial injection, and the pathogenicity of mosquito TMUV is higher than that of duck TMUV.2. TMUV can infect SPF ducklings by intramuscular injection, and the pathogenicity of duck TMUV is higher than that of mosquito TMUV.3. SPF ducklings infected with mosquito TMUV did not produce viremia at 3, 5 and 7 dpi.

Natural circulation of tick-borne severe fever with thrombocytopenia syndrome virus in the city ecosystem, China

Xing Zhang, Chaoyue Zhao, Xiaoxi Si, Qiang Hu, Aihua Zheng

2023, 38(5): 832 doi: 10.1016/j.virs.2023.08.004

Received: 28 May 2023 Accepted: 16 August 2023
Abstract [PDF 867 KB] ScienceDirect ESM
1. Hedgehogs and H. longicornis ticks can maintain the natural circulation of SFTSV in the city ecosystem.
2. Hedgehogs and H. longicornis ticks are becoming common in Beijing.
3. Parthenogenetic H. longicornis ticks are discovered in Beijing.