Genetic and mechanistic dissection of a lethal systemic virus infection

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 DESCRIPTION (provided by applicant): Systemic virus infections cause significant morbitity and mortality and are a significant worldwide health problem. People vary in disease outcome, and this is partly due to natural allelic variation throughout the genome. We are interested in better understanding how genomic elements outside of the MHC, TCR, and immunoglobulin regions regulate pathogenic outcomes to infection. The mouse arenavirus, LCMV-clone13, rapidly disseminates upon infection and causes limited pathogenesis in C57B6 mice. We have identified a substrain of B6 mouse that develops many characteristics of viral hemmoragic fever and systemic shock following infection, including severe weight loss, excessive cytokine production, and evidence of elevated tissue damage. These two strains are ~98% identical, but we have identified a 30Mb stretch on Chromosome 9 that and associates with the severe phenotype. The disease causing locus is dominantly inherited in F1 crosses and 100% penetrant. We hypothesize that the severe pathogenesis is caused by a single, gain-of-function gene in this region that exaggerates the antiviral T cell response. Here, we propose to identify the genetic mutation that causes severe pathogenesis after infection. The objectives of Aim1 are to use forward genetics coupled with bioinformatic approaches to narrow the disease-causing QTL to identify a small number of genes. We will examine whether genes within this interval are differentially expressed and whether there are global gene expression changes in T cells. The objectives of Aim2 are to determine whether the disease-causing genotype needs to be expressed by hematopoietic or non- hematopoietic cells to cause severe pathogenesis. Overall, this project will identify genetic loci that cause severe pathogenesis after systemic viru infection. These efforts will support a long-term endeavor to identify and characterize genetic elements that increase susceptibility to virus infection. This information is valuable for identifyng individuals at increased risk of disease after virus infection and for developing therapeutics to prevent severe pathogenesis following systemic virus infection.