A loss-of-function mutation inItgalcontributes to the high susceptibility of Collaborative Cross strain CC042 toSalmonellainfections
Authors: Zhang Jing , Teh Megan , Kim Jamie , Eva Megan M. , Cayrol Romain , Meade Rachel , Nijnik Anastasia , Montagutelli Xavier , Malo Danielle , Jaubert Jean 
Published: August 2019

AbstractSalmonellaare intracellular bacteria that are found in the gastrointestinal tract of mammalian, avian, and reptilian hosts. They are one of the leading causes of foodborne infections and a major threat for human populations worldwide. Mouse models have been extensively used to model distinct aspects of the humanSalmonellainfectionsin vivoand have led to the identification of several host susceptibility genes. We have investigated the susceptibility of Collaborative Cross strains to intravenous infection withSalmonellaTyphimurium 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, which are the precursors of T, B and NK cells. An F2 cross between CC042 and C57BL/6N identified two significant QTLs on chromosome 7 (Stsl6andStsl7) with WSB-derived susceptible alleles. A private variant in the integrin alpha L (Itgal) gene is carried by CC042 in theStsl7QTL region. A quantitative complementation test confirmed the impact ofItgalloss of function 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 theItgalgene.Author summarySalmonellaare one of the leading causes of foodborne infections and a major threat for human populations worldwide. Not all humans are equally susceptible toSalmonellainfection. Some individuals will develop minor symptoms and recover while others develop severe illness and might die. Mouse models are used to study distinct aspects of humanSalmonellainfectionin vivo. We used a new genetically diverse mouse population to investigate host susceptibility differences toSalmonellainfection. We identified one mouse strain with an extreme susceptibility to infection characterized by very high bacterial loads and mortality. Mice of this strain had small thymus and spleen, two organs which are very important for producing a fully mature immune system. We showed that the strain’s immune response is impaired and that its extreme susceptibility toSalmonellainfection is due to multiple genes defects. We identified a loss-of-function mutation in theItgalgene (Integrin Subunit Alpha L) that plays a central role in the immune response to infection. This gene explains part of the susceptibility and other gene(s) involved remain to be identified. Our results emphasize how new genetically diverse animal models can lead to the identification of new host genetic variants controlling susceptibility to pathogens and improve our understanding of human infections.