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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Oregon Health and Science University
United States
Zip Code
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

Showing the most recent 10 out of 75 publications