This U19 research grant application responds to the Immune Mechanisms of Virus Control (IMVC) RFA, and is comprised of four projects, an Administrative Core, and a Mouse Resources Core, integrated into a Program of study aimed at defining the immune mechanisms of flavivirus control. Flaviviruses present major and emerging public health threats, and they share common mechanisms of genome replication, host immune induction, and immune evasion strategies. Our work will encompass studies with Dengue virus (DENV), West Nile virus (WNV), and Japanese encephalitis virus (JEV). DENV, WNV, and JEV are among the most important mosquito-transmitted viruses globally. These viruses continually are emerging and can cause severe hemorrhagic (DENV) or neurological disease (WNV and JEV) in humans. There is no approved antiviral therapeutic agent available for treatment of flavivirus infections. Moreover, there are no approved vaccines against DENV or WNV infection for the billions of at-risk people, and the current JEV vaccines demonstrate limited durability. Thus, there is a great need to define the virus/host interactions of flavivirus control in order to identify therapeutic and vaccine strategies for treating or preventing infection. The studies in this U19 Program will investigate the overarching hypothesis that the outcome of flavivirus infection is determined by the balance of virus and host control of innate and adaptive immune programs. To investigate this hypothesis our Program will include studies on Project 1: Defining mechanisms of pathogen recognition and induction of innate immunity and inflammation against flavivirus infection; Project 2: Determining how innate immune responses impact entry, infection, and spread of encephalitic flaviviruses in the central nervous system; Project 3: Determining how innate immune responses program humoral immunity to flaviviruses; and Project 4: Defining the processes regulating T cell immunity against flavivirus infection. The management and research infrastructure support for the U19 Program will be coordinated though an Administrative Core and a Mouse Resources Core. Results from our studies will provide novel insights to guide vaccine and therapeutic strategies aimed at modulating flavivirus infection.
Dengue virus, West Nile virus, and Japanese encephalitis virus are members of the Flavivirus genus, and are the leading cause of mosquito-transmitted viral disease. These viruses continue to emerge and spread globally. Our studies will assess the virus and host interactions that regulate the innate immune and inflammatory responses to infection, and will reveal novel targets for the development of therapeutics against flaviviruses.
|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|
Showing the most recent 10 out of 147 publications