The role of MAVS signaling in humoral immune responses to West Nile virus.

Abstract

Abstract MAVS is a key regulator of innate immune responses to RNA viruses, such as West Nile virus (WNV). Previous work identified that MAVS is important for the development of adaptive immunity to WNV. MAVS KO mice are highly susceptible to infection with lethal WNV-Tx. MAVS KO mice produced significantly increased levels of WNV-specific IgM and IgG compared to WT mice, however, a corresponding increase in neutralizing antibodies (NAbs) was not observed. As MAVS KO mice succumb rapidly to WNV-Tx, it was not possible in our initial study to define the role of MAVS in the development of the germinal centers (GCs) as well as long-term plasma cell (PC) and memory B cell responses. Using the less pathogenic WNV-MAD, we examined the development of humoral responses in the absence of MAVS. MAVS KO mice survived infection with WNV-MAD, and as with WNV-Tx infection, produced increased levels of IgM and IgG but comparatively low levels of NAbs. This increase in serum Ab levels was maintained up to 9 weeks post-infection (pi). Moreover, the number of WNV-specific Ab secreting cells in the spleen and bone marrow were increased in MAVS KO mice compared to WT mice. Using flow cytometry we found that MAVS KO mice have a slight delay in expansion of GL7+ GC B cells, but by day 10 pi the number of GC B cells was about 10-fold higher than in WT mice. MAVS KO mice also showed a rapid expansion of IgM−CD138hi PCs that was significantly increased compared to WT mice. We are currently testing the hypothesis that these results are due to an intrinsic dysregulation of MAVS KO B cells rather than simply due to an increase in viral load. We are also examining both extrafollicular and GC responses to identify the basis for the rapid IgG antibody responses in MAVS KO mice. (Supported by NIH grant AI83019).