Project 1 is focused on understanding how virus and host control innate immune defenses and the outcome of West Nile (WNV) virus infection. West Nile virus is a model flavivirus. Its replication program, host immune induction, and innate immune evasion strategies, are representative of other members of the flavivirus family. WNV is emerging in the Western hemisphere, and is now a contemporary public health threat. Our studies have defined specific pathogen recognition (PRR) pathways and interferon regulatory factors (IRFs) as key features of immune triggering and programming during WNV infection. We hypothesize that viral triggering and control of PRR signaling programs and innate immune defenses of the host cell defines the tissue tropism and virulence properties of WNV infection. To investigate this hypothesis we will conduct in vitro and in vivo studies to 1) Define the cell-specific PRR pathways that trigger innate immunity against WNV infection; 2) Identify the interferon-stimulated innate immune effector genes that control WNV replication, and 3) Determine the molecular mechanisms by which pathogenic WNV evades the innate immune actions of alpha/beta interferons. In collaboration with Projects 2-5 and the Virology Core, we will define the role of the innate immune response in governing immunity and the outcome of WNV infection. These studies will define the virus/host interface of WNV infection that controls immunity, and will provide novel insights to guide vaccine and therapeutic strategies aimed at modulating WNV and flavivirus infection.
Flavivruses, including West Nile virus, are major and emerging human pathogens. Our studies will use West Nile virus as a model system to define the processes by which flaviviruses trigger and control innate immunity to infection. These studies will provide insights to direct therapeutic and vaccine strategies aimed at limiting flavivirus infection and disease.
| Chow, Kwan T; Wilkins, Courtney; Narita, Miwako et al. (2018) Differential and Overlapping Immune Programs Regulated by IRF3 and IRF5 in Plasmacytoid Dendritic Cells. J Immunol 201:3036-3050 |
| Bryan, Marianne A; Giordano, Daniela; Draves, Kevin E et al. (2018) Splenic macrophages are required for protective innate immunity against West Nile virus. PLoS One 13:e0191690 |
| Agner, Shannon C; Klein, Robyn S (2018) Viruses have multiple paths to central nervous system pathology. Curr Opin Neurol 31:313-317 |
| Green, Richard; Ireton, Reneé C; Gale Jr, Michael (2018) Interferon-stimulated genes: new platforms and computational approaches. Mamm Genome 29:593-602 |
| Walker, Christie L; Merriam, Audrey A; Ohuma, Eric O et al. (2018) Femur-sparing pattern of abnormal fetal growth in pregnant women from New York City after maternal Zika virus infection. Am J Obstet Gynecol 219:187.e1-187.e20 |
| Hahn, William O; Butler, Noah S; Lindner, Scott E et al. (2018) cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses. JCI Insight 3: |
| Garber, Charise; Vasek, Michael J; Vollmer, Lauren L et al. (2018) Astrocytes decrease adult neurogenesis during virus-induced memory dysfunction via IL-1. Nat Immunol 19:151-161 |
| Bowen, James R; Zimmerman, Matthew G; Suthar, Mehul S (2018) Taking the defensive: Immune control of Zika virus infection. Virus Res 254:21-26 |
| Johnson, Britney; VanBlargan, Laura A; Xu, Wei et al. (2018) Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability. Immunity 48:487-499.e5 |
| 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: |
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