Date Published: June 26, 2019
Publisher: Public Library of Science
Author(s): Kelsey Roe, Daniela Giordano, Lucy B. Young, Kevin E. Draves, Ursula Holder, Mehul S. Suthar, Michael Gale, Edward A. Clark, Teunis B. H. Geijtenbeek.
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.
The mosquito-borne neurotropic flavivirus West Nile virus (WNV) is the most important cause of epidemic viral encephalitis in North America. Although neutralizing antibodies (nAbs) are essential for protection after infection with WNV or related flaviviruses such as Dengue virus and Zika virus, relatively little is known about what early events after flavivirus infection are required in innate immune cells to program protective Ab responses. Flavivirus infection is recognized by the RIG-I-like receptor (RLR) pathogen recognition receptor proteins, RIG-I and MDA5 [1,2]. The RLRs bind viral RNA and undergo activation events to then bind to the signaling adaptor protein MAVS. RLR binding to MAVS induces signaling to activate downstream transcription factors that direct the expression of immune modulatory genes, antiviral genes, and the production of types I and III interferon (IFN) [3–5]. IFN then induces the expression of interferon stimulated genes (ISGs). 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].
In this study we evaluated the role that the innate adaptor molecule MAVS plays in the development of humoral immune responses during WNV infection. In order to study the long-term antibody responses during WNV infection in the absence of MAVS, we first determined that MAVS-deficient mice can survive a non-pathogenic WNV-MAD infection (Fig 1). In contrast, IFNAR-deficient mice die after footpad inoculation with 100 PFU of WNV-MAD ; furthermore, WNV-MAD can be lethal when inoculated intracranially into WT mice [19,20]. The fact that MAVS-/- mice control WNV-MAD infection and IFNAR-/- mice do not , is most likely due to the fact that MAVS-/- mice still make type I IFN after WNV infection, possibly downstream of TLR activation, and thus, presumably utilize the IFNAR pathway for protection .