Rift Valley fever virus is a Category A arbovirus pathogen that causes hemorrhagic fever, retinitis and encephalitis in Africa and the Middle East. The virus has high potential for deliberate release and bioterrorism since it may be aerosolized and transmitted by inhalation or contact with mucosal tissue as well as by blood-feeding mosquitoes. Given the lack of a small animal model that faithfully recapitulates the diverse outcomes of human infection and the fact that RVF epidemics occur in remote areas, little is known about how innate immune events contribute to disease pathogenesis and protective adaptive immunity aside from limited observations that delayed type I IFN responses are associated with severe illness and mortality. These gaps in knowledge will be addressed by combining study of residents of an area of Kenya where RVF epidemics occur in ~8-year cycles (most recently 2006-2007) with in vitro models of infection and disease pathogenesis. We have observed that RVFV transmission to humans in this area is much greater than previously suspected, both during epidemic and inter-epidemic periods, with up to 25% lifetime risk of infection.
In Specific Aim 1 we will define the risk factors for and spectrum of chronic disease phenotypes (primarily retinitis) in persons infected during earlier, repeated RVF epidemics and pre-position the necessary systems to test panels of patients with and without RVF-associated encephalitis and/or hemorrhagic fever during the next epidemic.
In Specific Aim 2 we will use in vitro models to define the innate immune pathways, e.g. TLR and RNA helicases, affected by attenuated RVFV, identify key cellular targets at sites of viral inoculation, dissemination and pathogenesis, e.g. oral and conjunctiva epithelium, dendritic cells, retinal pigmented epithelium and venous endothelium, and examine how attenuated RVFV alters the ability of dendritic cells to present antigen to T cells.
In Specific Aim 3 we will examine the relationship between serologic markers of prior infection and RVFV-specific CD4+ and CD8+ T cell memory, identify viral epitopes that elicit T cell memory, and correlate in vitro PBMC innate and adaptive immune responses to RVFV epitopes with the development of retinitis.
In Specific Aim 4 we will determine how genetic polymorphism of innate immunity accounts for heterogeneity in retinitis outcomes and adaptive immunity. Overall this project will provide novel information regarding how innate and adaptive immunity to RVFV determines infection and disease outcomes in humans at high-risk for exposure to this Category A pathogen.
This project is relevant to the central theme of the MRCE concerned with innate immunity to biodefense pathogens and advances human translational research concerned with understanding how innate and adaptive immunity protect against infection and contribute to disease pathogenesis of a Category A Bunyavirus that has high potential for bioterrorism.
|Stevenson, Taylor C; Cywes-Bentley, Colette; Moeller, Tyler D et al. (2018) Immunization with outer membrane vesicles displaying conserved surface polysaccharide antigen elicits broadly antimicrobial antibodies. Proc Natl Acad Sci U S A 115:E3106-E3115|
|Kinkead, Lauren C; Whitmore, Laura C; McCracken, Jenna M et al. (2018) Bacterial lipoproteins and other factors released by Francisella tularensis modulate human neutrophil lifespan: Effects of a TLR1 SNP on apoptosis inhibition. Cell Microbiol 20:|
|Kinkead, Lauren C; Fayram, Drew C; Allen, Lee-Ann H (2017) Francisella novicida inhibits spontaneous apoptosis and extends human neutrophil lifespan. J Leukoc Biol 102:815-828|
|Zhao, Guoyan; Wu, Guang; Lim, Efrem S et al. (2017) VirusSeeker, a computational pipeline for virus discovery and virome composition analysis. Virology 503:21-30|
|Das, Anshuman; Hirai-Yuki, Asuka; González-López, Olga et al. (2017) TIM1 (HAVCR1) Is Not Essential for Cellular Entry of Either Quasi-enveloped or Naked Hepatitis A Virions. MBio 8:|
|Grinnage-Pulley, Tara; Mu, Yang; Dai, Lei et al. (2016) Dual Repression of the Multidrug E?ux Pump CmeABC by CosR and CmeR in Campylobacter jejuni. Front Microbiol 7:1097|
|Ulland, Tyler K; Jain, Nidhi; Hornick, Emma E et al. (2016) Nlrp12 mutation causes C57BL/6J strain-specific defect in neutrophil recruitment. Nat Commun 7:13180|
|Markosyan, Ruben M; Miao, Chunhui; Zheng, Yi-Min et al. (2016) Induction of Cell-Cell Fusion by Ebola Virus Glycoprotein: Low pH Is Not a Trigger. PLoS Pathog 12:e1005373|
|Teijaro, John R; Studer, Sean; Leaf, Nora et al. (2016) S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-? autoamplification. Proc Natl Acad Sci U S A 113:1351-6|
|Lubman, Olga Y; Fremont, Daved H (2016) Parallel Evolution of Chemokine Binding by Structurally Related Herpesvirus Decoy Receptors. Structure 24:57-69|
Showing the most recent 10 out of 338 publications