The SIDT2/MDA5/IFN axis contributes to virus resistance in teleost fish

Disease resistance varies among fish species. The genetic factors contributing to disease resistance are largely unknown. Here, by comparative analysis on the disease resistance trait of grass carp (Ctenopharyngodon idellus, Ci) and barbel chub (Squaliobarbus curriculus, Sc), we report that the genes encoding SIDT2, MDA5 and IFN are associated with the resistance to viral infection. We identified the amino acid difference of SIDT2s, the existing or lacking of dsRNA binding loci in the carboxy-terminal domain (CTD) of MDA5s, and the promoter difference of ifn2s between the two fish species. Both CiSIDT2 and ScSIDT2 negatively regulate the MDA5-IRF3/7 mediated type I IFN reaction, and ScSIDT2 exhibited a stronger ability than CiSIDT2 to induce Ciirf7, Ciifn1, Ciifn2 and Cimx expressions, and to resist GCRV infection. ScMDA5 showed a greater ability than CiMDA5 in the induction of IRF7-mediated type I interferon and anti-GCRV function. CiMDA5 CTD inhibited Ciifn1 while enhanced Ciifn2 exrpessions, and ScMDA5 CTD exerts opposite effects on Ciifn1 and Ciifn2 expressions. ScMDA5 CTD possesses the ability to bind with GCRV nucleic acid fragments, while CiMDA5 lacking binding with virus genome. The promoter activities of Ciifn2 is significantly higher than that of Scifn2 owning to their differences in promoter sequences and binding proteins. These data revealed the mechanism of SIDT2-MDA5-IFN genetic architecture contributing to the difference in interspecies resistance and opening the possibility of molecular breeding for fish resistance.