Genetic background influences survival of infections with Salmonella enterica serovar Typhimurium in the Collaborative Cross

Abstract

Salmonella infections typically cause self-limiting gastroenteritis, but in some individuals these bacteria can spread systemically and cause disseminated disease. Salmonella Typhimurium (STm), which causes severe systemic disease in most inbred mice, has been used as a model for disseminated disease. To screen for new infection phenotypes across a range of host genetics, we orally infected 32 Collaborative Cross (CC) mouse strains with STm and monitored their disease progression for seven days by telemetry. Our data revealed a broad range of phenotypes across CC strains in many parameters including survival, bacterial colonization, tissue damage, complete blood counts (CBC), and serum cytokines. Eighteen CC strains survived to day 7, while fourteen susceptible strains succumbed to infection before day 7. Several CC strains had sex differences in survival and colonization. Surviving strains had lower pre-infection baseline temperatures and were less active during their daily active period. Core body temperature disruptions were detected earlier after STm infection than activity disruptions, making temperature a better detector of illness. All CC strains had STm in spleen and liver, but susceptible strains were more highly colonized. Tissue damage was weakly negatively correlated to survival. We identified loci associated with survival on Chromosomes (Chr) 1, 2, 4, 7. Polymorphisms in Ncf2 and Slc11a1, known to reduce survival in mice after STm infections, are located in the Chr 1 interval, and the Chr 7 association overlaps with a previously identified QTL peak called Ses2. We identified two new genetic regions on Chr 2 and 4 associated with susceptibility to STm infection. Our data reveal the diversity of responses to STm infection across a range of host genetics and identified new candidate regions for survival of STm infection. Author SummarySalmonella Typhimurium (STm) infections typically cause self-limiting diarrheal symptoms, but in some individuals, the bacteria can spread throughout the body and cause life-threatening infection. We used a population of genetically different mice (Collaborative Cross) to identify their range of responses to STm infection. We identified a broad range of outcomes across these different mice, including a group of mice susceptible to lethal infection and a group that survived our 7 day study. We found that mice that survived STm infection had a cooler core body temperature before infection than susceptible mice, while remaining active. Thus, body temperature, rather than activity, appears to be a better predictor of poor outcomes after STm infection. We identified several regions of the mouse genome that are associated with outcome after STm infection. One of these regions, mouse Chromosome (Chr) 1 has genes that are already known to influence susceptibility to STm infection. Two other regions that we identified to influence survival after STm infection, located on mouse Chr 2 and 4, are novel and contain numerous genes of interest that may be linked to susceptibility. Our work defines the utility of exploring how host genetic diversity influences infection outcomes with bacterial pathogens.