MAVS regulates the quality of the antibody response to West-Nile Virus

Abstract

1A key difference that distinguishes viral infections from protein immunizations is the 2 recognition of viral nucleic acids by cytosolic pattern recognition receptors (PRRs) such as RNA-3 sensing Rig-I-like receptors (RLRs). Insights into the specific functions of cytosolic PRRs in the 4 instruction of adaptive immunity are therefore critical for the understanding of protective immunity 5 to infections. West Nile virus (WNV) infection of mice deficent of MAVS, the essential RLR 6 signaling adaptor, results in a defective adaptive immune response. While this finding suggests a 7 role for RLRs in the instruction of adaptive immunity to WNV, it is difficult to interpret due to the 8 high WNV viremia, associated exessive antigen loads, and pathology in the absence of a MAVS-9 dependent innate immune response. To overcome these limitations, we have infected MAVS-10 deficient mice with a single-round-of-infection mutant of WNV called RepliVAX (RWN). RWN-11 infected MAVS-deficient (MAVS KO ) mice failed to produce an effective neutralizing antibody 12 response to WNV despite normal titers of antibodies targeting the viral WNV-E protein. This defect 13 occurred indepedently of antigen loads or overt pathology. The specificity of the antibody 14 response in RWN-infected MAVS KO mice remained unchanged and was still dominated by 15 antibodies that bound the neutralizing lateral ridge (LR) epitope in the DIII domain of WNV-E. 16Instead, MAVS KO mice produced IgM antibodies, the dominant isotype controlling primary WNV 17 infection, with lower affinity for the DIII domain. Our findings suggest that RLR-dependent signals 18 are important for the quality of the humoral immune response to WNV.