This project develops a systems genetics approach using genetically defined recombinant inbred (Rl) rodent challenge models (collaborative cross mice-CC) that capture 90% of the natural genetic variation in the mouse, a unique resource capable of untangling polygenic, complex disease traits. This infection model will be coupled with genomics, proteomics, and reverse genetics and used as a platform technology to identify the virus-host interactions and susceptibility alleles that regulate highly pathogenic respiratory virus induced severe and end-stage lung disease in young and senescent animals. This platform will be used for a comparative pathogenomics approach focused on SARS-CoV, mouse-adapted influenza virus, and highly pathogenic avian influenza viruses. The goal is to compare and contrast the host susceptibility alleles and signaling circuitry that enhance pneumotropic virus replication and pathogenesis with the goal of identifying common key cellular targets that influence severe disease outcomes by diverse respiratory pathogens. To verify the importance of these alleles and signaling pathways in severe lung disease, we will model and empirically test disease outcomes using genetically defined virus mutants, siRNA knockdown techniques, CC recombinant inbred strains and select knockout animals. Finally, we evaluate the role of select common susceptibility alleles in siRNA-treated primates infected with SARS-CoV or high-path influenza viruses. Consequently, we will systematically test the hypothesis that genetic medicine and systems pathogenomics can predict disease outcomes in individuals, identify susceptibility alleles governing severe end-stage lung disease, uncover the role of specific viral genes in host signaling, and provide fundamental insights into the critical host circuitry that promotes efficient virus replication and virulence in the lung.
impact of this work is very high, providing the first definitive studies that identify polygenetic traits associated with complex disease outcomes following acute severe respiratory tract infections in mammals. The research provides a predictive format for determining if genetic medicine can predict disease outcomes prior to infection with various respiratory viruses and potentially identifies key cell signaling pathways which regulate mild or severe disease outcomes in individuals.
|Smithey, Megan J; Venturi, Vanessa; Davenport, Miles P et al. (2018) Lifelong CMV infection improves immune defense in old mice by broadening the mobilized TCR repertoire against third-party infection. Proc Natl Acad Sci U S A 115:E6817-E6825|
|Maurizio, Paul L; Ferris, Martin T; Keele, Gregory R et al. (2018) Bayesian Diallel Analysis Reveals Mx1-Dependent and Mx1-Independent Effects on Response to Influenza A Virus in Mice. G3 (Bethesda) 8:427-445|
|Uhrlaub, Jennifer L; Smithey, Megan J; Nikolich-Žugich, Janko (2017) Cutting Edge: The Aging Immune System Reveals the Biological Impact of Direct Antigen Presentation on CD8 T Cell Responses. J Immunol 199:403-407|
|Pryke, Kara M; Abraham, Jinu; Sali, Tina M et al. (2017) A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses. MBio 8:|
|Kebaabetswe, Lemme P; Haick, Anoria K; Gritsenko, Marina A et al. (2015) Proteomic analysis reveals down-regulation of surfactant protein B in murine type II pneumocytes infected with influenza A virus. Virology 483:96-107|
|Sanchez, Erica L; Lagunoff, Michael (2015) Viral activation of cellular metabolism. Virology 479-480:609-18|
|Kell, Alison M; Gale Jr, Michael (2015) RIG-I in RNA virus recognition. Virology 479-480:110-21|
|Fontaine, Krystal A; Sanchez, Erica L; Camarda, Roman et al. (2015) Dengue virus induces and requires glycolysis for optimal replication. J Virol 89:2358-66|
|Rasmussen, Angela L; Tchitchek, Nicolas; Safronetz, David et al. (2015) Delayed inflammatory and cell death responses are associated with reduced pathogenicity in Lujo virus-infected cynomolgus macaques. J Virol 89:2543-52|
|Morgan, Andrew P; Welsh, Catherine E (2015) Informatics resources for the Collaborative Cross and related mouse populations. Mamm Genome 26:521-39|
Showing the most recent 10 out of 127 publications