The long-term goal of this project is to understand host responses to Ebolavirus infections. To address this question, we propose a 'Systems Biology1 approach that will use mouse and macaque infection models, cell culture and biochemical assays, and high-throughput genomic and proteomic analyses to identify cellular response networks to Ebolavirus infection, and the underlying features of protective immunity afforded by successful vaccination.
In Aim 1, we will assess the contribution of RIG-I and TLR3/7-signaling to innate immune responses to Ebolavirus infection. RIG-I and TLR3/7 signaling pathways are now recognized as major players in innate immune responses;their significance for innate immune responses to Ebolavirus infections, however, is currently unknown and will therefore be addressed in this aim. To identify additional host response networks that critically affect the outcome of Ebolavirus infections, we will test wild-type and mutant Ebolaviruses in wild-type, knock-out, and genetically diverse mice in Aim 2;the latter studies will allow the identification of host susceptibility alleles. Ebolavirus mutants will include variants possessing mutations in the VP24 and VP35 proteins which are known to affect the interferon antagonist activity of these proteins. Moreover, we will carry out infection, genomics, proteomics, and metabolomics studies in nonhuman primates, the gold standard for filovirus infection studies.
In Aim 3, we plan to determine the mechanisms of protective immune responses induced by Ebolavirus vaccines. The availability of a candidate vaccine that protects mice and nonhuman primates from challenge with lethal doses of Ebolavirus will allow us to dissect the underlying mechanisms for protection. Collectively, the proposed studies will provide novel insights into the network of host responses that determine the outcome of Ebolavirus infections, and may thus suggest novel approaches to the treatment of Ebolavirus infections.

Public Health Relevance

Currently, there are no licensed vaccines or antiviral compounds to prevent or treat Ebolavirus infections. The proposed studies will provide a better understanding of host responses to Ebolavirus infections, and may hence suggest novel targets for the development of antiviral compounds.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZAI1-DDS-M)
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Oregon Health and Science University
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Smith, Jessica L; Stein, David A; Shum, David et al. (2014) Inhibition of dengue virus replication by a class of small-molecule compounds that antagonize dopamine receptor d4 and downstream mitogen-activated protein kinase signaling. J Virol 88:5533-42
Trobaugh, Derek W; Gardner, Christina L; Sun, Chengqun et al. (2014) RNA viruses can hijack vertebrate microRNAs to suppress innate immunity. Nature 506:245-8
Haick, Anoria K; Rzepka, Joanna P; Brandon, Elizabeth et al. (2014) Neutrophils are needed for an effective immune response against pulmonary rat coronavirus infection, but also contribute to pathology. J Gen Virol 95:578-90
Gibbs, David L; Gralinski, Lisa; Baric, Ralph S et al. (2014) Multi-omic network signatures of disease. Front Genet 4:309
Gardner, Christina L; Hritz, Jozef; Sun, Chengqun et al. (2014) Deliberate attenuation of chikungunya virus by adaptation to heparan sulfate-dependent infectivity: a model for rational arboviral vaccine design. PLoS Negl Trop Dis 8:e2719
Josset, Laurence; Tchitchek, Nicolas; Gralinski, Lisa E et al. (2014) Annotation of long non-coding RNAs expressed in collaborative cross founder mice in response to respiratory virus infection reveals a new class of interferon-stimulated transcripts. RNA Biol 11:875-90
Nikolich-┼Żugich, Janko (2014) Aging of the T cell compartment in mice and humans: from no naive expectations to foggy memories. J Immunol 193:2622-9
Engelmann, Flora; Josset, Laurence; Girke, Thomas et al. (2014) Pathophysiologic and transcriptomic analyses of viscerotropic yellow fever in a rhesus macaque model. PLoS Negl Trop Dis 8:e3295
Pal, Pankaj; Fox, Julie M; Hawman, David W et al. (2014) Chikungunya viruses that escape monoclonal antibody therapy are clinically attenuated, stable, and not purified in mosquitoes. J Virol 88:8213-26
Fontaine, Krystal A; Camarda, Roman; Lagunoff, Michael (2014) Vaccinia virus requires glutamine but not glucose for efficient replication. J Virol 88:4366-74

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