The use of pathogen recognition receptor (PRR) agonists and the molecular mechanisms 31 involved have been the major focus of research in individual vaccine development. West Nile 32 virus (WNV) nonstructural (NS) 4B-P38G mutant has several features for an ideal vaccine 33 candidate, including significantly reduced neuroinvasiveness, induction of strong adaptive 34 immunity, and protection of mice from wild-type (WT) WNV infection. Here, we determined 35 the role of mitochondrial antiviral-signaling (MAVS), the adaptor protein for RIG-I like receptor in regulating host immunity against the NS4B-P38G vaccine. We found that Mavs−/− 36 mice were more susceptible to NS4B-P38G priming than WT mice. Mavs−/− 3... More
The use of pathogen recognition receptor (PRR) agonists and the molecular mechanisms 31 involved have been the major focus of research in individual vaccine development. West Nile 32 virus (WNV) nonstructural (NS) 4B-P38G mutant has several features for an ideal vaccine 33 candidate, including significantly reduced neuroinvasiveness, induction of strong adaptive 34 immunity, and protection of mice from wild-type (WT) WNV infection. Here, we determined 35 the role of mitochondrial antiviral-signaling (MAVS), the adaptor protein for RIG-I like receptor in regulating host immunity against the NS4B-P38G vaccine. We found that Mavs−/− 36 mice were more susceptible to NS4B-P38G priming than WT mice. Mavs−/− 37 mice had a transiently reduced production of antiviral cytokines, and an impaired CD4+ 38 T cell response in peripheral organs. However, antibody and CD8+ 39 T cell responses were minimally affected. NS4B-P38G induced 40 lower type I interferon (IFN), IFN stimulating gene, and proinflammatory cytokine responses in Mavs−/− dendritic cells, and subsequently compromised antigen presenting capacity for CD4+ 41 T cells. Interestingly, Mavs−/− 42 mice surviving NS4B-P38G priming were all protected from a lethal WT WNV challenge. NS4B-P38G- primed Mavs−/− 43 mice exhibited equivalent levels of protective CD4+ 44 T cell recall response, a modestly reduced WNV-specific IgM production, but more robust CD8+ 45 T cell recall response. Taken together, our results suggest that MAVS is essential for boosting optimal primary CD4+ 46 T cell responses upon NS4B-P38G vaccination, yet 47 is dispensable for host protection and recall T cell responses during secondary WT WNV 48 infection.
