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

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 coinfection 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.

Fish herpesvirus KLP manipulates Beclin1 to selectively degrade MITA through a precise autophagic manner for immune evasion

Control of host autophagy acceleration or attenuation has been confirmed in multiple terrestrial animal viruses.Little is known about such mechanisms in aquatic viruses.Here,we report a selective and ingenious autophagy modulation regulated by kinase-like protein(KLP)of cyprinid herpesvirus 2(CyHV2)to restrict interferon(IFN)production by degrading IFN regulatory factor(IRF)3 activation(MITA).First,exogenous DNA and RNAmediated IFN activation were both abrogated by CyHV2 KLP.The common intersection point of MITA with these two signaling pathways was the interaction with KLP.The C terminus of MITA was indispensable for the interaction and was recruited by KLP in subcellular colocalization analysis.Subsequently,we found that KLP degraded MITA in an autophagy-lysosome-dependent manner and,interestingly,individual KLP could not launch host autophagic flow except in the presence of MITA.KLP was also colocalized with the autophagy components Beclin1 and ATG14 and enhanced Beclin1 stability,but not ATG14,through K63-linked polyubiquitination.Finally,KLP significantly decreased the normal state or MITA-enhanced cellular antiviral capacity.These data demonstrated an elaborate autophagic process manipulated by a fish virus only in the presence of the host target,illuminating a mechanism of aquatic viral immune evasion.