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.
|Bekerman, Elena; Neveu, Gregory; Shulla, Ana et al. (2017) Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects. J Clin Invest 127:1338-1352|
|Daniels, Brian P; Jujjavarapu, Harsha; Durrant, Douglas M et al. (2017) Regional astrocyte IFN signaling restricts pathogenesis during neurotropic viral infection. J Clin Invest 127:843-856|
|Da Costa, Andreia; Garza, Esteban; Graham, Jessica B et al. (2017) Extrinsic MAVS signaling is critical for Treg maintenance of Foxp3 expression following acute flavivirus infection. Sci Rep 7:40720|
|Gorman, Jacquelyn A; Hundhausen, Christian; Errett, John S et al. (2017) The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity. Nat Immunol 18:744-752|
|Jagger, Brett W; Miner, Jonathan J; Cao, Bin et al. (2017) Gestational Stage and IFN-? Signaling Regulate ZIKV Infection In Utero. Cell Host Microbe 22:366-376.e3|
|Daniels, Brian P; Snyder, Annelise G; Olsen, Tayla M et al. (2017) RIPK3 Restricts Viral Pathogenesis via Cell Death-Independent Neuroinflammation. Cell 169:301-313.e11|
|Li, Junwei; Baird, Madison A; Davis, Michael A et al. (2017) Dramatic enhancement of the detection limits of bioassays via ultrafast deposition of polydopamine. Nat Biomed Eng 1:|
|Luo, Huanle; Winkelmann, Evandro; Xie, Guorui et al. (2017) MAVS Is Essential for Primary CD4+ T Cell Immunity but Not for Recall T Cell Responses following an Attenuated West Nile Virus Infection. J Virol 91:|
|Tajfirouz, Deena; West, Devin M; Yin, Xiao-Tang et al. (2017) CXCL9 compensates for the absence of CXCL10 during recurrent Herpetic stromal keratitis. Virology 506:7-13|
|Green, Richard; Wilkins, Courtney; Thomas, Sunil et al. (2017) Oas1b-dependent Immune Transcriptional Profiles of West Nile Virus Infection in the Collaborative Cross. G3 (Bethesda) 7:1665-1682|
Showing the most recent 10 out of 120 publications