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.

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.

To survive a bacterial infection, an infected host can display resistance or tolerance. Resistance is indicated by a decrease in pathogen load, while for tolerance a high pathogen load is accompanied by minimal disease.

Recent developments in both biological data acquisition and analysis provide new opportunities for data-driven modelling of the health state of an organism. In this paper, we explore the evolution of temperature patterns generated by telemetry data collected from healthy and infected mice. We investigate several techniques to visualize and identify anomalies in temperature time series as temperature relates to the onset of infectious disease. Visualization tools such as Laplacian Eigenmaps and Multidimensional Scaling allow one to gain an understanding of a dataset as a whole. Anomaly detection tools for nonlinear time series modelling, such as Radial Basis Functions and Multivariate State Estimation Technique, allow one to build models representing a healthy state in individuals. We illustrate these methods on an experimental dataset of 306 Collaborative Cross mice challenged with Salmonella typhimurium and show how interruption in circadian patterns and severity of infection can be revealed directly from these time series within 3 days of the infection event.

Background: The human gut microbiota is a complex community comprised of trillions of bacteria and is critical for the digestion and absorption of nutrients. Bacterial communities of the intestinal microbiota influence the development of several conditions and diseases. We studied the effect of host genetics on gut microbial composition using Collaborative Cross (CC) mice, a panel of genetically diverse mouse strains. CC mice are genetically diverse across strains, but genetically identical within a given strain allowing for repetition and deeper analysis than is possible with other collections of genetically diverse mice. Results: 16S rRNA from the feces of 167 mice from 28 different CC strains was sequenced and analyzed using the Qiime2 pipeline. We observed large variance in the bacterial composition across CC strains starting at the phylum level. Using bacterial composition data, we identified 26 significant Quantitative Trait Locus (QTL) linked to 23 genera on 15 different mouse chromosomes. Genes within these intervals were analyzed for significant association with pathways and the previously known human GWAS database using Enrichr and DAVID analysis. Multiple host genes involved in obesity, glucose homeostasis, immunity, neurological diseases, and many other protein-coding genes located in these regions may play roles in determining the composition of the gut microbiota. After the collection of feces used for sequencing, a subset of CC mice was infected with Salmonella Typhimurium. Using the infection outcome data, we correlated the increase in abundance of Genus Lachnospiraceae and decrease in Genus Parasutterella to positive health outcomes after infection. Machine learning classifiers accurately predicted the CC strain and the infection outcome using pre-infection bacterial composition data from the feces. Conclusion: Our study supports the hypothesis that multiple host genes influence the gut microbiome composition and homeostasis, and that certain organisms may influence health outcomes after S. Typhimurium infection.