Infect Immun 62:2702C2706. reduced total number of thymocytes and double-negative and double-positive (CD4+, CD8+) thymocytes compared to C57BL/6J mice. Analysis of GSK744 (S/GSK1265744) bone marrow-resident hematopoietic progenitors showed a strong bias against lymphoid-primed multipotent progenitors. An F2 cross between CC042 and C57BL/6N mice recognized two loci on chromosome 7 (and region, CC042 carried a loss-of-function variant, unique to this strain, in the integrin alpha L (loss of function increased the susceptibility to Typhimurium in a (C57BL/6J CC042)F1 mouse background but not in a C57BL/6J mouse inbred background. These results further emphasize the power of the Collaborative Cross to identify new host genetic variants controlling susceptibility to infections and improve our understanding of the function of the gene. is usually a relatively common Gram-negative bacterium that is generally transmitted via the consumption of contaminated food or water (1). Contamination with can lead to a variety of pathologies, with worldwide health and economic costs. Human-restricted serovars GSK744 (S/GSK1265744) serovar Typhi GREM1 and Typhimurium, lead to 93.8 million cases of gastroenteritis annually (5). Symptoms of gastroenteritis involve diarrhea, vomiting, and nausea (1). In immunocompromised patients, nontyphoidal strains can also result in systemic and invasive infections including bacteremia and sepsis (6). The study of in mouse models is typically conducted with Typhimurium, as it is known to induce systemic infections in mice similar to the bacteremia observed in immunocompromised patients (1). After systemic contamination with Typhimurium, the bacteria are rapidly cleared from your bloodstream (within 2?h), followed by localization of approximately 10% of the inoculum within macrophages and polymorphonuclear cells of visceral organs, such as the spleen and liver, where it can replicate efficiently. In order to handle the producing systemic contamination, the host must activate a strong innate and adaptive immune response (1, 7). Many factors are known to be involved in the clinical outcomes and the ability of the host to clear contamination in both humans and mouse models. Factors include the bacterial strain, the dosage of contamination, and the host immune status, microbiome, and genetic makeup (1, 6, 8, 9). Host genetics are progressively being GSK744 (S/GSK1265744) recognized as a crucial element involved in host susceptibility to contamination. While many genes, such as those for Toll-like receptor 4 (TLR4), interleukin 12 (IL-12), and transmission transducer and activator of GSK744 (S/GSK1265744) transcription 4 (STAT4), have been implicated in the response to contamination in human populations (13,C15). One approach utilized for the detection of novel genes involved in complex traits, such as susceptibility, utilizes a murine genetic reference population known as the Collaborative Cross (CC) (16). While traditional models tend to use highly homogeneous mouse populations, the CC has been designed to model the range of genetic variance of the human population (17). The CC is usually a panel of recombinant inbred mice derived from eight founder strains, including five laboratory strains and three wild-derived inbred strains (18), resulting in highly variable phenotypes. The genomes of the CC strains feature relatively well dispersed recombination sites and balanced allele origins from all eight founder strains (19), allowing for the genetic dissection of complex traits (20). Moreover, the CC serves as a platform to develop improved models of infectious disease and to map loci associated with variations in susceptibility to pathogens (21). We previously utilized the CC to demonstrate that host genetic factors contribute to significant variations in susceptibility (22). Following challenge of 35 CC strains with Typhimurium, we showed that this bacterial burdens of the spleen and liver were significantly different between strains (22). One strain in particular, GSK744 (S/GSK1265744) known as CC042/GeniUnc (CC042), was shown to be extremely susceptible to Typhimurium contamination, with greater than 1,000-fold higher figures CFU being found in the spleen and liver of these mice compared to the figures found in the highly susceptible C57BL/6J (B6) reference strain (22). It has been shown that a missense mutation in.