. doi: 10.1016/j.virs.2022.12.003
Citation: Zhuo-Cong Li, Long-Feng Lu, Can Zhang, Xue-Li Wang, Jin-Feng Tong, Ke-Jia Han, Dan-Dan Chen, Xi-Yin Li, Li Zhou, Jian-Fang Gui, Shun Li. GCRV NS38 counteracts SVCV proliferation by intracellular antagonization during co-infection .VIROLOGICA SINICA, 2023, 38(1) : 142-156.  http://dx.doi.org/10.1016/j.virs.2022.12.003

GCRV NS38在复合感染期间通过胞内拮抗作用抑制SVCV增殖

  • 通讯作者: 李顺, bob@ihb.ac.cn
  • 收稿日期: 2022-09-10
    录用日期: 2022-12-07
  • 病毒复合感染在动物中时有发生,然而,复合感染的机制尚不清楚。水体中病毒的丰富性和多样性使鱼类极易受到复合感染。在这里,我们报道了一种使斑马鱼死亡率降低的复合感染情况,并阐明了两种病毒复合感染的细胞内分子机制。鲤春病毒血症病毒(SVCV)是一种高致病性病毒,可感染鲤科鱼类,如斑马鱼。当与草鱼呼肠孤病毒(GCRV)复合感染时,SVCV感染导致的斑马鱼死亡率显著降低,组织损伤的严重程度和病毒增殖也有所降低。转录组生物信息学分析表明,复合感染显著缓解SVCV感染对斑马鱼体内转录水平的影响。在排除这两种病毒的细胞外相互作用后,我们进一步探索机制发现,GCRV非结构蛋白NS38显著抑制SVCV病毒增殖。NS38与SVCV核蛋白(N)和磷蛋白(P)蛋白相互作用,同时抑制N和P蛋白表达。后续分析表明,N蛋白被NS38降解过程中,自噬受体p62是不可或缺的。同时,NS38通过降低P蛋白k63连接的多聚泛素化,导致了P蛋白的泛素化降解。上述结果揭示了细胞内病毒蛋白相互作用是复合感染的重要机制,并导致宿主病理反应的变化。该研究拓展了我们对细胞内病毒相互作用复合感染的认识,对鱼类病毒复合感染研究具有重要启示。

GCRV NS38 counteracts SVCV proliferation by intracellular antagonization during co-infection

  • Corresponding author: Shun Li, bob@ihb.ac.cn
  • Received Date: 10 September 2022
    Accepted Date: 07 December 2022
  • Viral co-infection has been found in animals; however, the mechanisms of co-infection are unclear. The abundance and diversity of viruses in water make fish highly susceptible to co-infection. Here, we reported a co-infection in fish, which resulted in reduced host lethality and illustrated the intracellular molecular mechanism of viral co-infection. The spring viremia of carp virus (SVCV) is a highly lethal virus that infects Cyprinidae, such as zebrafish. The mortality of SVCV infection was significantly reduced when co-infected with the grass carp reovirus (GCRV). The severity of tissue damage and viral proliferation of SVCV was also reduced in co-infection with GCRV. The transcriptome bioinformatics analysis demonstrated that the effect on the host transcripts in response to SVCV infection was significantly reduced in co-infection. After excluding the extracellular interactions of these two viruses, the intracellular mechanisms were studied. We found that the GCRV NS38 remarkably decreased SVCV infection and viral proliferation. The interaction between GCRV NS38 and SVCV nucleoprotein (N) and phosphoprotein (P) proteins was identified, and NS38 downregulated both N and P proteins. Further analysis demonstrated that the N protein was degraded by NS38 indispensable of the autophagy receptor, sequestosome 1 (p62). Meanwhile, K63-linked ubiquitination of the P protein was reduced by NS38, leading to ubiquitinated degradation of the P protein. These results reveal that the intracellular viral protein interactions are a crucial mechanism of co-infection and influence the host pathology and expand our understanding in intracellular viral interactions co-infection.

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    1. Arora U, Garg P, Agarwal S, Nischal N, Shalimar, Wig N. 2021. Complexities in the treatment of coinfection with hiv, hepatitis b, hepatitis c, and tuberculosis. Lancet Infect Dis, 21:e399-e406.

    2. Arzt J, Fish IH, Bertram MR, Smoliga GR, Hartwig EJ, Pauszek SJ, Holinka-Patterson L, Diaz-San Segundo FC, Sitt T, Rieder E, Stenfeldt C. 2021. Simultaneous and staggered foot-and-mouth disease virus coinfection of cattle. J Virol, 95:e0165021.

    3. Bai L, Zhao Y, Dong J, Liang S, Guo M, Liu X, Wang X, Huang Z, Sun X, Zhang Z, Dong L, Liu Q, Zheng Y, Niu D, Xiang M, Song K, Ye J, Zheng W, Tang Z, Tang M, Zhou Y, Shen C, Dai M, Zhou L, Chen Y, Yan H, Lan K, Xu K. 2021. Coinfection with influenza a virus enhances sars-cov-2 infectivity. Cell Res, 31:395-403.

    4. Brodin P, Arditi M. 2022. Severe acute hepatitis in children:Investigate sars-cov-2 superantigens. Lancet Gastroenterol Hepatol, 7:594-595.

    5. Bruhn JF, Hotard AL, Spiropoulou CF, Lo MK, Saphire EO. 2019. A conserved basic patch and central kink in the nipah virus phosphoprotein multimerization domain are essential for polymerase function. Structure, 27:660-668 e664.

    6. Deng Z, Li X, Blanca Ramirez M, Purtell K, Choi I, Lu JH, Yu Q, Yue Z. 2021. Selective autophagy of akap11 activates camp/pka to fuel mitochondrial metabolism and tumor cell growth. Proc Natl Acad Sci U S A, 118:e2020215118.

    7. Deng ZQ, Purtell K, Lachance V, Wold MS, Chen S, Yue ZY. 2017. Autophagy receptors and neurodegenerative diseases. Trends in Cell Biology, 27:491-504.

    8. Domingos JA, Shen X, Terence C, Senapin S, Dong HT, Tan MR, Gibson-Kueh S, Jerry DR. 2021. Scale drop disease virus (sddv) and lates calcarifer herpes virus (lchv) coinfection downregulate immune-relevant pathways and cause splenic and kidney necrosis in barramundi under commercial farming conditions. Front Genet, 12:666897.

    9. Ernst J, Bar-Joseph Z. 2006. Stem:A tool for the analysis of short time series gene expression data. BMC Bioinformatics, 7:191.

    10. Griffiths EC, Pedersen AB, Fenton A, Petchey OL. 2011. The nature and consequences of coinfection in humans. J Infect, 63:200-206.

    11. Gul-Seker M, Elibuyuk IO. 2019. Occurrence of tomato yellow leaf curl virus and tomato chlorosis virus mixed infections in protected tomato plants, antalya, turkey. Phytoparasitica, 47:441-449.

    12. Gupta N, Rao PV. 2011. Transcriptomic profile of host response in japanese encephalitis virus infection. Virol J, 8:92.

    13. Hofmann RM, Pickart CM. 2001. In vitro assembly and recognition of lys-63 polyubiquitin chains. J Biol Chem, 276:27936-27943.

    14. Hoque MN, Rahman MS, Ahmed R, Hossain MS, Islam MS, Islam T, Hossain MA, Siddiki AZ. 2021. Diversity and genomic determinants of the microbiomes associated with covid-19 and non-covid respiratory diseases. Gene Rep, 23:101200.

    15. Hoshino T, Nishima D, Enseki M, Umehara N, Fukasawa C, Ishiwada N. 2022. Pediatric parapneumonic effusion/pleural empyema in japan:A nationwide survey. Pediatr Infect Dis J, 41:20-23.

    16. Jones BA, Mahapatra M, Chubwa C, Clarke B, Batten C, Hicks H, Henstock M, Keyyu J, Kock R, Parida S. 2020. Characterisation of peste des petits ruminants disease in pastoralist flocks in ngorongoro district of northern tanzania and bluetongue virus co-infection. Viruses, 12:389.

    17. Kim HT, Kim KP, Lledias F, Kisselev AF, Scaglione KM, Skowyra D, Gygi SP, Goldberg AL. 2007. Certain pairs of ubiquitin-conjugating enzymes (e2s) and ubiquitin-protein ligases (e3s) synthesize nondegradable forked ubiquitin chains containing all possible isopeptide linkages. J Biol Chem, 282:17375-17386.

    18. Kirkpatrick DS, Hathaway NA, Hanna J, Elsasser S, Rush J, Finley D, King RW, Gygi SP. 2006. Quantitative analysis of in vitro ubiquitinated cyclin b1 reveals complex chain topology. Nat Cell Biol, 8:700-710.

    19. Koh C, Da BL, Glenn JS. 2019. Hbv/hdv coinfection:A challenge for therapeutics. Clin Liver Dis, 23:557-572.

    20. Kondratowicz AS, Lennemann NJ, Sinn PL, Davey RA, Hunt CL, Moller-Tank S, Meyerholz DK, Rennert P, Mullins RF, Brindley M, Sandersfeld LM, Quinn K, Weller M, McCray PB, Chiorini J, Maury W. 2011. T-cell immunoglobulin and mucin domain 1 (tim-1) is a receptor for zaire ebolavirus and lake victoria marburgvirus. Proceedings of the National Academy of Sciences of the United States of America, 108:8426-8431.

    21. Kotob MH, Menanteau-Ledouble S, Kumar G, Abdelzaher M, El-Matbouli M. 2016. The impact of co-infections on fish:A review. Vet Res, 47:98.

    22. Langford BJ, So M, Raybardhan S, Leung V, Westwood D, MacFadden DR, Soucy JR, Daneman N. 2020. Bacterial co-infection and secondary infection in patients with covid-19:A living rapid review and meta-analysis. Clin Microbiol Infect, 26:1622-1629.

    23. Li S, Lu LF, Wang ZX, Lu XB, Chen DD, Nie P, Zhang YA. 2016. The p protein of spring viremia of carp virus negatively regulates the fish interferon response by inhibiting the kinase activity of tank-binding kinase 1. J Virol, 90:10728-10737.

    24. Li S, Lu LF, Liu SB, Zhang C, Li ZC, Zhou XY, Zhang YA. 2019. Spring viraemia of carp virus modulates p53 expression using two distinct mechanisms. PLoS Pathog, 15:e1007695.

    25. Lu LF, Li S, Wang ZX, Du SQ, Chen DD, Nie P, Zhang YA. 2017. Grass carp reovirus vp41 targets fish mita to abrogate the interferon response. J Virol, 91:e00390-17.

    26. Lu LF, Li S, Lu XB, LaPatra SE, Zhang N, Zhang XJ, Chen DD, Nie P, Zhang YA. 2016. Spring viremia of carp virus n protein suppresses fish ifnphi1 production by targeting the mitochondrial antiviral signaling protein. J Immunol, 196:3744-3753.

    27. Lu LF, Zhang C, Li ZC, Zhou XY, Jiang JY, Chen DD, Zhang YA, Xiong F, Zhou F, Li S. 2021. A novel role of zebrafish tmem33 in negative regulation of interferon production by two distinct mechanisms. PLoS Pathog, 17:e1009317.

    28. McBride R, van Zyl M, Fielding BC. 2014. The coronavirus nucleocapsid is a multifunctional protein. Viruses-Basel, 6:2991-3018.

    29. McCullers JA. 2014. The co-pathogenesis of influenza viruses with bacteria in the lung. Nat Rev Microbiol, 12:252-262.

    30. Nickbakhsh S, Mair C, Matthews L, Reeve R, Johnson PCD, Thorburn F, von Wissmann B, Reynolds A, McMenamin J, Gunson RN, Murcia PR. 2019. Virus-virus interactions impact the population dynamics of influenza and the common cold. Proc Natl Acad Sci U S A, 116:27142-27150.

    31. Nishitha Y, Priyanka E, Vamshi Krishna S, Kannaki TR. 2021. Co-infection of marek's disease virus with different oncogenic immunosuppressive viruses in chicken flocks. Virusdisease, 32:804-809.

    32. Palinski RM, Brito B, Jaya FR, Sangula A, Gakuya F, Bertram MR, Pauszek SJ, Hartwig EJ, Smoliga GR, Obanda V, Omondi GP, VanderWaal K, Arzt J. 2022. Viral population diversity during co-infection of foot-and-mouth disease virus serotypes sat1 and sat2 in african buffalo in kenya. Viruses, 14:897.

    33. Pei C, Ke F, Chen ZY, Zhang QY. 2014. Complete genome sequence and comparative analysis of grass carp reovirus strain 109 (gcrev-109) with other grass carp reovirus strains reveals no significant correlation with regional distribution. Arch Virol, 159:2435-2440.

    34. Rosenberg BR, Depla M, Freije CA, Gaucher D, Mazouz S, Boisvert M, Bedard N, Bruneau J, Rice CM, Shoukry NH. 2018. Longitudinal transcriptomic characterization of the immune response to acute hepatitis c virus infection in patients with spontaneous viral clearance. PLoS Pathog, 14:e1007290.

    35. Saeki Y, Kudo T, Sone T, Kikuchi Y, Yokosawa H, Toh-e A, Tanaka K. 2009. Lysine 63-linked polyubiquitin chain may serve as a targeting signal for the 26s proteasome. EMBO J, 28:359-371.

    36. Simkova A, Civanova K, Vetesnik L. 2022. Heterosis versus breakdown in fish hybrids revealed by one-parental species-associated viral infection. Aquaculture, 546:737406.

    37. Sulkowski MS. 2008. Viral hepatitis and hiv coinfection. J Hepatol, 48:353-367.

    38. Tao MM, Liu T, You QD, Jiang ZY. 2020. P62 as a therapeutic target for tumor. European Journal of Medicinal Chemistry, 193:112231.

    39. Tso CH, Lu MW. 2018. Transcriptome profiling analysis of grouper during nervous necrosis virus persistent infection. Fish Shellfish Immunol, 76:224-232.

    40. Vidalain PO, Tangy F. 2010. Virus-host protein interactions in rna viruses. Microbes Infect, 12:1134-1143.

    41. Wang D, Mai J, Yang Y, Xiao CT, Wang N. 2022. Current knowledge on epidemiology and evolution of novel porcine circovirus 4. Vet Res, 53:38.

    42. Wolf YI, Silas S, Wang Y, Wu S, Bocek M, Kazlauskas D, Krupovic M, Fire A, Dolja VV, Koonin EV. 2020. Doubling of the known set of rna viruses by metagenomic analysis of an aquatic virome. Nat Microbiol, 5:1262-1270.

    43. Xu LM, Liu M, Zhao JZ, Ren GM, Dong Y, Shao YZ, Lu TY, Zhang QY. 2020. Infectious pancreatic necrosis virus inhibits infectious hematopoietic necrosis virus at the early stage of infection in a time dependent manner during co-infection in chinook salmon embryo cell lines. Fish Shellfish Immunol, 102:361-367.

    44. Xu T, Hou CY, Zhang YH, Li HX, Chen XM, Pan JJ, Chen HY. 2022. Simultaneous detection and genetic characterization of porcine circovirus 2 and 4 in henan province of china. Gene, 808:145991.

    45. Zhang F, Zhu H, Wu Y, Dou Z, Zhang Y, Kleinman N, Bulterys M, Wu Z, Ma Y, Zhao D, Liu X, Fang H, Liu J, Cai WP, Shang H. 2014. Hiv, hepatitis b virus, and hepatitis c virus co-infection in patients in the china national free antiretroviral treatment program, 2010-12:A retrospective observational cohort study. Lancet Infect Dis, 14:1065-1072.

    46. Zhang QY, Gui JF. 2015. Virus genomes and virus-host interactions in aquaculture animals. Science China-Life Sciences, 58:156-169.

    47. Zhang QY, Gui JF. 2018. Diversity, evolutionary contribution and ecological roles of aquatic viruses. Science China-Life Sciences, 61:1486-1502.

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    GCRV NS38 counteracts SVCV proliferation by intracellular antagonization during co-infection

      Corresponding author: Shun Li, bob@ihb.ac.cn
    • a. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China;
    • b. University of Chinese Academy of Sciences, Beijing, 100049, China;
    • c. State Key Laboratory of Freshwater Ecology and Biotechnology, Hubei Hongshan Laboratory, The Innovation Academy of Seed Design, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China;
    • d. College of Fisheries and Life Science, Dalian Ocean University, Dalian, 116023, China

    Abstract: Viral co-infection has been found in animals; however, the mechanisms of co-infection are unclear. The abundance and diversity of viruses in water make fish highly susceptible to co-infection. Here, we reported a co-infection in fish, which resulted in reduced host lethality and illustrated the intracellular molecular mechanism of viral co-infection. The spring viremia of carp virus (SVCV) is a highly lethal virus that infects Cyprinidae, such as zebrafish. The mortality of SVCV infection was significantly reduced when co-infected with the grass carp reovirus (GCRV). The severity of tissue damage and viral proliferation of SVCV was also reduced in co-infection with GCRV. The transcriptome bioinformatics analysis demonstrated that the effect on the host transcripts in response to SVCV infection was significantly reduced in co-infection. After excluding the extracellular interactions of these two viruses, the intracellular mechanisms were studied. We found that the GCRV NS38 remarkably decreased SVCV infection and viral proliferation. The interaction between GCRV NS38 and SVCV nucleoprotein (N) and phosphoprotein (P) proteins was identified, and NS38 downregulated both N and P proteins. Further analysis demonstrated that the N protein was degraded by NS38 indispensable of the autophagy receptor, sequestosome 1 (p62). Meanwhile, K63-linked ubiquitination of the P protein was reduced by NS38, leading to ubiquitinated degradation of the P protein. These results reveal that the intracellular viral protein interactions are a crucial mechanism of co-infection and influence the host pathology and expand our understanding in intracellular viral interactions co-infection.

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