Using a reduced complexity cross to identify host susceptibility factors to SARS-CoV infection Lisa E. Gralinski1, Kenneth Dinnon III2, Timothy Bell3, Martin T Ferris3, Fernando Pardo Manuel de Villena3, Ralph S Baric1 1Epidemiology Department, University of North Carolina at Chapel Hill, 2Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, 3Genetics Department, University of North Carolina at Chapel Hill
Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) was identified in 2002 as the etiologic agent of a global outbreak of atypical pneumonia and acute respiratory distress syndrome. The host factors contributing to either survival or progression to severe disease remain unknown. To address this question, we used a systems genetics approach driven by the serendipitous observation that Balb/cJ mice are resistant to infection with SARS-CoV while Balb/cByJ mice are extremely susceptible. Taking advantage of recent genotyping advances and the close genetic relationship between these substrains, we designed an F2 cross between the resistant Balb/cJ and susceptible Balb/cByJ to enable mapping of host alleles guiding the response to SARS-CoV infection. 266 mice were infected with SARS-CoV and monitored during a four day infection. We observed that susceptibility to SARS-CoV infection was dominant and that weight loss and pulmonary hemorrhage were significantly correlated (p<0.001) while weight loss and pulmonary titer were not correlated (p=0.5608). We identified a single quantitative trait locus of major effect on chromosome 15 that effected day four weight loss. After mapping with existing SNP markers this QTL covers a 48Mb region that includes 189 novel variants between Balb/cJ and Balb/cByJ in 103 genes or intergenic regions. Testing additional Balb/c substrains reduced the candidate genes by over 75% and currently we are narrowing the QTL interval using PCR based fine mapping. Given the small number of variants we anticipate identifying both the gene and the causative mutation that dictate the varying Balb/c responses to SARS-CoV infection. Analysis of the early response to infection in susceptible and resistant Balb/c substrains suggests that aberrant immune signaling may be responsible for the differential infection outcome. In addition to improving our understanding of SARS-CoV pathogenesis, this work highlights the care that must be taken in comparing phenotypes between mouse substrains.
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