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

Abstract

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

A yellow fever virus NS4B inhibitor not only suppresses viral replication, but also enhances the virus activation of RIG-I-like receptor-mediated innate immune response

“…WNV infection of RIG-I and MDA5 double-knockout mice or MAVS knockout mice failed to induce innate immune response and scrubbed to the viral infection [ 34 ]. In addition to the enhanced viral replication and dissemination with early viral entry into the central nerve system, WNV infected MAVS knockout mice demonstrated uncontrolled inflammatory cytokine/chemokine response due to the lack of the expansion of regulatory T cells and lack of neutralization antibody production [ 62 , 63 ]. Although deficiency of RIG-I, MDA5 or MAVS in HEK293 cells only modestly increased the levels of YFV RNA ( S6 Fig ), the RLR pathway has been shown to play a critical role in the control of flavivirus infection and immunopathogenesis in vivo.…”

Exposure of negative-sense viral RNA in the cytoplasm initiates innate immunity to West Nile virus

“…A549 IRF3KO cells (4x10 5 cells) were transfected with 100ng of total RNA extracted from replicon-bearing BHK21 cells 37 using Transit-mRNA transfection kit (Mirus Bio) with a 1:1 ratio of RNA:Transit-mRNA reagent. Cells were selected for successful transfection at 48h post transfection with media containing 400ug/mL G418 (Fisher Scientific).…”

“…During WNV infection, the initiation of an antiviral innate immune response is critical for viral clearance and engagement of the adaptive immune response 3 . Previous studies form our lab and others have shown that the RIG-I-like receptor (RLR) family of pathogen recognition receptors are critical for initiating the antiviral response to WNV infection and programming the adaptive immune response both in vitro and in vivo [4][5][6][7] .…”