Although neutralizing antibodies (NAbs) are essential for protection after infection of many flaviviruses, relatively little is known about the key early events in innate immune cells that lead to effective neutralizing Ab responses. RIG-I like receptor (RLR) family members sense viral RNA and through the mitochondria associated adaptor protein MAVS, induce antiviral responses including the production of type I interferons (IFNs). Both MAVS and type I IFN pathways regulate Ab responses to viruses. In Project 3 we will determine the specific cell types that require MAVS and the type I IFN receptor (IFNAR) signaling to help develop the rapid first line Ab defense to WNV and later germinal center-dependent high affinity and long-lived NAb and memory B cell responses. Using a set of conditional knockout mice with either MAVS or IFNAR deleted in a cell type restricted manner, we will determine how MAVS or IFNAR function in dendritic cells (DCs), macrophages or B cells help develop effective humoral immunity to West Nile virus (WNV), an encephalitic flavivirus featured in this U19 program. As BAFF, a type I IFN-inducible cytokine, is essential for normal B cell development and responses to antigens, we also will define the role ofthe BAFF receptors, BAFFR and BCMA in humoral immune responses to WNV and determine which cells must produce BAFF for long-lived immunity to develop. Finally, as both monocytes and macrophages play important roles in both innate and adaptive responses to flaviviruses, we define how and when these cells contribute to flavivirus humoral immunity using mouse models in which subsets of these cells are deleted. Overall, this work will provide new insights in the interface between the innate immune and humoral responses, which may facilitate novel strategies for creating optimal humoral vaccine responses against flaviviruses.
More than 90% of all effective vaccines induce highly effective and long-lasting protective antibody (Ab) responses. Neutralizing Abs play an important role in protective immunity to flaviviruses, including yellow fever, Japanese encephalitis. West Nile and Dengue viruses. This proposal will use genetically altered mice to identify what key sensors are important in specific cells for mice to develop long-lived Ab protection to WNV. New information on how best to develop novel vaccines to flaviviruses may stem from this work.
|Pierson, Theodore C; Diamond, Michael S (2018) The emergence of Zika virus and its new clinical syndromes. Nature 560:573-581|
|Adams Waldorf, Kristina M; Nelson, Branden R; Stencel-Baerenwald, Jennifer E et al. (2018) Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain. Nat Med 24:368-374|
|Hickman, Heather D; Suthar, Mehul S (2018) Editorial overview: Viral immunology: Generating immunity to diverse viral pathogens. Curr Opin Virol 28:viii-x|
|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|
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