Dendritic cells are critical for regulating T cell immune responses during virus infection. DCs provide the three necessary signals for optimal T cell activation, which include antigen presentation (signal 1), co-stimulation (signal 2), and inflammatory cytokines (signal 3). In turn, this leads to rapid T cell proliferation, clonal expansion, differentiation into effector cells, and formation of memory T cells, that combined, are critical for effective pathogen clearance and protection against re-infection. Type I interfero, regulated by the innate immune sensors of viral infection, play a key role in activation of innate and adaptive immune responses during virus infection. However, it is not clear how innate immune sensing regulates protective T cell immune responses during virus infection. We study West Nile virus (WNV) infection, a neurotropic mosquito-borne flavivirus of significant public health concern throughout the world, to dissect the viral and host factors that govern immunity to infection. Following WNV infection of DCs, the RLRs induce a robust type I interferon- mediated antiviral innate immune response that is critical for controlling virus replication. We recently discovered that the RLR LGP2, which lacks the critical caspase-activation and recruitment domains required for innate immune signaling, was found to function in a T cell-intrinsic manner to promote CD8+ T cell survival and effector functions. The absence of LGP2 in CD8+ T cells led to enhanced cell surface expression of death receptors, activation of extrinsic apoptosis signaling, and reduced cytokine secretion. Surprisingly, the protein mitochondrial antiviral signaling (MAVS), which is the essential adaptor to RLR signaling and a known binding partner of LGP2, was not required for promoting T cell survival. These findings demonstrate that LGP2 functions in a MAVS-independent manner to promote T cell immunity. Our studies have defined a key role for the RLRs at the interface between innate (DCs) and adaptive (T cells) immunity during virus infection. However, the mechanism underlying RLR regulation of T cell immunity is not well understood. In this proposal, we will evaluate two specific hypotheses: (1) The RLRs'function within DCs to regulate activation, function, and T cell priming during WNV infection;and (2) LGP2 functions within CD4+ and CD8+ T cells to regulate protective effector and memory immune responses during WNV infection. These proposed studies will likely reveal a broader role for the RLRs as well as uncover new pathways by which host RNA helicases regulate immunity during virus infection. This proposal likely will reveal new therapeutic targets and strategies for vaccine protection against flavivirus infection.
West Nile virus is a neurotropic mosquito-borne flavivirus of significant public health concern throughout the world. Our studies will investigate the crosstalk between innate immune sensing and regulation of protective T cell immune responses during WNV infection. These studies will reveal new therapeutic targets and strategies for vaccine protection against flavivirus infection.
|Bowen, James R; Zimmerman, Matthew G; Suthar, Mehul S (2018) Taking the defensive: Immune control of Zika virus infection. Virus Res 254:21-26|
|Aguilar-Valenzuela, Renan; Netland, Jason; Seo, Young-Jin et al. (2018) Dynamics of Tissue-Specific CD8+ T Cell Responses during West Nile Virus Infection. J Virol 92:|
|Bowen, James R; Quicke, Kendra M; Maddur, Mohan S et al. (2017) Zika Virus Antagonizes Type I Interferon Responses during Infection of Human Dendritic Cells. PLoS Pathog 13:e1006164|
|Quicke, Kendra M; Diamond, Michael S; Suthar, Mehul S (2017) Negative regulators of the RIG-I-like receptor signaling pathway. Eur J Immunol 47:615-628|
|Bowen, James R; Ferris, Martin T; Suthar, Mehul S (2016) Systems biology: A tool for charting the antiviral landscape. Virus Res 218:2-9|
|Priyamvada, Lalita; Quicke, Kendra M; Hudson, William H et al. (2016) Human antibody responses after dengue virus infection are highly cross-reactive to Zika virus. Proc Natl Acad Sci U S A 113:7852-7|
|Quicke, Kendra M; Bowen, James R; Johnson, Erica L et al. (2016) Zika Virus Infects Human Placental Macrophages. Cell Host Microbe 20:83-90|
|Seo, Young-Jin; Jothikumar, Prithiviraj; Suthar, Mehul S et al. (2016) Local Cellular and Cytokine Cues in the Spleen Regulate In Situ T Cell Receptor Affinity, Function, and Fate of CD8+ T Cells. Immunity 45:988-998|
|Gokhale, Nandan S; McIntyre, Alexa B R; McFadden, Michael J et al. (2016) N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection. Cell Host Microbe 20:654-665|
|Ma, Daphne Y; Suthar, Mehul S (2015) Mechanisms of innate immune evasion in re-emerging RNA viruses. Curr Opin Virol 12:26-37|