Systems Biology Approaches to Viral Pathogenesis and Immunity

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This Project builds upon the strengths of the Katze laboratory in genomics, proteomics, and bioinformatics to develop systems level views of the virus-host interactions and viral and host genetic determinants that regulate and determine the outcome of infection. To achieve this goal, we will work closely with investigators from the University of North Carolina (Project 3.1) and the University of Wisconsin (Project 3.2) who will be using infection models of SARS-CoV, influenza, and Ebola viruses. In addition to the extensive amount of microarray data that we will be collecting on these infection models, we will integrate proteomics, metabolomics, and lipidomics data that will also be available for selected infection models. In Aim 1, we will use gene expression data to obtain expression quantitative trait loci (eQTL) mapping in screens of 400 genetically distinct mice, comparing the infection outcomes with SARS-CoV, influenza, and Ebola viruses. Aim 2 generates a systems level view of viral virulence and disease progression from more detailed animal models; data integration is a key aspect to make optimal use of genomic and proteomic data for better understanding gene and protein function, as well as discerning how gene expression and protein abundance changes correlate with innate and adaptive immune responses and eventual disease outcome. In Aim 3, we will use genomic approaches to furnish a comprehensive view of the changes in host gene expression that occur in response to the Ebola virus immunization regimens described in Project 3.2. These data may suggest genomic markers of protective immunity or indicate the predisposition of an animal to a particular response to immunization and subsequent challenge. Together, these aims provide an integrated approach that markedly enhances synergy among the collaborating projects by allowing us and our collaborators to place experimental findings in the context of a more comprehensive picture of the infection process. In addition, our high-throughput studies are likely to provide molecular signatures that predict protective immunity or pathology, candidate biomarkers for diagnostic or prognostic assays, and a rational basis for improvements to antiviral therapies or vaccine strategies.