A loss-of-function mutation in the integrin alpha L (Itgal) gene contributes to susceptibility to Salmonella Typhimurium infection in Collaborative Cross strain CC042

Salmonella are intracellular bacteria found in the gastrointestinal tract of mammalian, avian, and reptilian hosts.. Mouse models have been extensively used to model in vivo distinct aspects of the human Salmonella infections and have led to the identification of several host susceptibility genes. We have investigated the susceptibility of Collaborative Cross strains to intravenous infection with Salmonella Typhimurium as a model of human systemic invasive infection. In this model, strain CC042 displayed extreme susceptibility with very high bacterial loads and mortality. CC042 mice showed lower spleen weight and decreased splenocyte numbers before and after infection, affecting mostly CD8+ T cells, B cells, and all myeloid populations. Uninfected mice also had lower thymus weight with reduced total number of thymocytes and double negative and (CD4+, CD8+) double positive thymocytes. Analysis of bone marrow resident hematopoietic progenitors showed a strong bias against lymphoid primed multipotent progenitors. An F2 cross between CC042 and C57BL/6N identified two loci on chromosome 7 (Stsl6 and Stsl7) associated with differences in bacterial loads. In the Stsl7 region, CC042 carries a loss-of-function variant unique to this strain in the integrin alpha L (Itgal) gene, which causative role was confirmed by a quantitative complementation test. Notably Itgal loss of function increased the susceptibility to S. Typhimurium in a (C57BL/6JxCC042)F1 background, but not in a C57BL/6J inbred background. These results further emphasize the utility of the Collaborative Cross to identify new host genetic variants controlling susceptibility to infections and improve our understanding of the function of the Itgal gene.