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Abstract
Mitochondrial antiviral signaling protein (MAVS) is a critical innate immune signaling protein that directs the actions of the RIG-I-like receptor (RLR) signaling pathway of RNA virus recognition and initiation of anti-viral immunity against West Nile virus (WNV). In the absence of MAVS, mice die more rapidly after infection with the pathogenic WNV-Texas (TX) strain, but also produce elevated WNV-specific IgG concomitant with increased viral burden. Here we investigated whether there was a B cell intrinsic role for MAVS during the development of protective humoral immunity following WNV infection. MAVS-/- mice survived infection from the non-pathogenic WNV-Madagascar (MAD) strain, with limited signs of disease. Compared to wildtype (WT) controls, WNV-MAD-infected MAVS-/- mice had elevated serum neutralizing antibodies, splenic germinal center B cells, plasma cells and effector T cells. We found that when rechallenged with the normally lethal WNV-TX, MAVS-/- mice previously infected with WNV-MAD were protected from disease. Thus, protective humoral and cellular immune responses can be generated in absence of MAVS. Mice with a conditional deletion of MAVS only in CD11c+ dendritic cells phenocopied MAVS whole body knockout mice in their humoral responses to WNV-MAD, displaying elevated virus titers and neutralizing antibodies. Conversely, a B cell-specific deletion of MAVS had no effect on immune responses to WNV-MAD compared to WT controls. Thus, MAVS in dendritic cells is required to control WNV replication and thereby regulate downstream humoral immune responses.
Highlights
The mosquito-borne neurotropic flavivirus West Nile virus (WNV) is the most important cause of epidemic viral encephalitis in North America
Mitochondrial antiviral signaling protein (MAVS)-/- mice all succumb to pathogenic lineage 1 WNV-TX infection within 8–9 days due to their inability to control virus replication and spread into the central nervous system [9]
In order to investigate the development of long-term humoral responses to WNV in the absence of MAVS and to address if MAVS plays an intrinsic role in B cells after WNV infection, we first tested whether or not MAVS-/- mice could survive infection of a less pathogenic form of WNV, WNV Madagascar 78 (WNV-MAD) [11,12]
Summary
The mosquito-borne neurotropic flavivirus West Nile virus (WNV) is the most important cause of epidemic viral encephalitis in North America. ISG products have antiviral and immune-modulatory actions that serve to regulate the onset and actions of the adaptive immune responses Innate immunity, and both humoral and T cell immunity are essential for the control of WNV infection and neuropathogenesis [1,4,6]. Type I IFN receptor (IFNAR) and type III IFN receptor are expressed on a variety of cell types and are signaled in turn to activate ISG expression across a variety of tissues, leading to strong anti-viral responses and programming of adaptive immunity [3,6,7]. Despite having much higher levels of virus-specific Abs, the nAb titers in MAVS-/- mice were not that much higher than titers detected in infected WT mice This result suggested that MAVS regulates the quantity of IgG Ab responses to WNV, and the quality of the Ab response, such as Ab affinity. Conditional knockout (cKO) mice with MAVS-deficiency restricted to CD11c+ dendritic cells (DCs) had a similar phenotype as MAVS-/- mice, underscoring the critical role MAVS plays in DCs in programming resistance to WNV and probably other viruses
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