Regulation of Antibody Responses against West Nile Virus by the Innate Signaling Adaptor MAVS

Abstract

The activation of pattern recognition receptors (PRRs) is a major regulatory checkpoint for the generation of adaptive immunity. Rig-I-like Receptors (RLRs) comprise a PRR family that includes the RNA helicases RIG-I and MDA-5, which recognize microbial RNA in the cytosol. RLR activation induces antiviral effector programs in infected cells and lead to the release of proinflammatory cytokines and interferons. RLRs are therefore important mediators of the innate immune response to many viral infections. However, the role of RLRs in the regulation of adaptive immunity is still poorly understood. Infection of mice deficient in MAVS, the essential signaling adaptor of RLRs, with West Nile Virus (WNV) results in a defective adaptive immune response. While this finding suggests a role for RLRs in the control of adaptive immunity to WNV, it is difficult to interpret due to high WNV titers in the absence of a MAVS-dependent innate immune response. In order to overcome this caveat, we have infected MAVSKO mice with a replication-incompetent mutant of WNV. Here, we report a defect in the neutralizing antibody response to WNV in the absence of MAVS despite the presence of normal WNV-specific antibody titers. This defect was accompanied by an increased number of Tfh cells and an enlarged germinal center (GC) B cell compartment in the draining lymph nodes. Our data show that the epitope specificity of the antibody response to WNV is unchanged in MAVSKO mice and instead implicate the presence of low avidity antibodies as the cause for the inefficient neutralization of WNV. Together, our findings suggest that RLR -dependent signals regulate humoral immunity to WNV infection.