| dc.description.abstract | Salmonella Typhimurium (STm) usually cause self-limiting gastroenteritis. In some individuals, these bacteria can spread systemically and cause disseminated disease. Rising incidence of antibiotic resistance in STm is a world-wide health concern. Exploration of disease phenotypes that differ between individuals may offer alternative pathways for treatment of infections that do not rely on traditional antibiotics. We screened 32 Collaborative Cross (CC) lines for their responses to oral infection with STm to discover new pathways involved in response to infection and host disease outcome. Eighteen CC lines survived to day 7, while fourteen required euthanasia before day 7. The surviving 18 lines were infected and monitored for three weeks. Five of these lines reduced the bacterial load and were called resistant, 6 lines maintained a bacterial load and were categorized as tolerant, and 7 lines succumbed to infection before three-weeks and were called delayed susceptible. The tolerant lines maintained bacterial burdens in Peyer’s patches (PP), mesenteric lymph node (MLN), spleen, and liver, while resistant lines had significantly lower colonization in multiple tissues. Surviving mice had lower baseline temperatures than susceptible mice at one week post-infection and tolerant lines had lower baseline temperatures than both delayed susceptible and resistant. Resistant lines reduced tissue damage in spleen and liver while tolerant lines did not repair tissue damage between one and three weeks post-infection. We identified four suggestive loci for one-week survival, and one significant and six suggestive associations for three-week phenotypes. CC045 was particularly unusual as it survived one-week infections with high bacterial loads and modest weight loss, unlike other lines carrying the Slc11a1 mutation. We generated an Slc11a1- F2 population between CC045 and CC061. F1s all survived infection as did the majority of the F2s, supporting a dominant phenotype. The F2s were highly colonized in spleen and liver while maintaining body weight better than CC061, the parental susceptible line. Genetic analysis was performed on the survival data and four significant associations, and one significant allele interaction were identified. | |
