25Salmonella are intracellular bacteria that are found in the gastrointestinal tract of mammalian, 26 avian, and reptilian hosts. They are one of the leading causes of foodborne infections and a major 27 threat for human populations worldwide. Mouse models have been extensively used to model 28 distinct aspects of the human Salmonella infections in vivo and have led to the identification of 29 several host susceptibility genes. We have investigated the susceptibility of Collaborative Cross 30 strains to intravenous infection with Salmonella Typhimurium as a model of human systemic 31 invasive infection. In this model, strain CC042 displayed extreme susceptibility with very high 32 bacterial loads and mortality. CC042 mice showed lower spleen weight and decreased splenocyte 33 numbers before and after infection, affecting mostly CD8 + T cells, B cells, and all myeloid 34 populations. Uninfected mice also had lower thymus weight with reduced total number of 35 thymocytes and double negative and (CD4 + , CD8 + ) double positive thymocytes. Analysis of 36 bone marrow resident hematopoietic progenitors showed a strong bias against lymphoid primed 37 multipotent progenitors, which are the precursors of T, B and NK cells. An F2 cross between 38 CC042 and C57BL/6N identified two significant QTLs on chromosome 7 (Stsl6 and Stsl7) with 39 WSB-derived susceptible alleles. A private variant in the integrin alpha L (Itgal) gene is carried 40 by CC042 in the Stsl7 QTL region. A quantitative complementation test confirmed the impact of 41 Itgal loss of function in a (C57BL/6JxCC042)F1 background, but not in a C57BL/6J inbred 42 background. These results further emphasize the utility of the Collaborative Cross to identify 43 new host genetic variants controlling susceptibility to infections and improve our understanding 44 of the function of the Itgal gene. 45 46 3 47 Author summary 48 Salmonella are one of the leading causes of foodborne infections and a major threat for human 49 populations worldwide. Not all humans are equally susceptible to Salmonella infection. Some 50 individuals will develop minor symptoms and recover while others develop severe illness and 51 might die. Mouse models are used to study distinct aspects of human Salmonella infection in 52vivo. We used a new genetically diverse mouse population to investigate host susceptibility 53 differences to Salmonella infection. We identified one mouse strain with an extreme 54 susceptibility to infection characterized by very high bacterial loads and mortality. Mice of this 55 strain had small thymus and spleen, two organs which are very important for producing a fully 56 mature immune system. We showed that the strain's immune response is impaired and that its 57 extreme susceptibility to Salmonella infection is due to multiple genes defects. We identified a 58 loss-of-function mutation in the Itgal gene (Integrin Subunit Alpha L) that plays a central role in 59 the immune response to infection. This gene explains part of the susceptibility and other gene(s) 60 in...