The role of the intestinal microbiota in host susceptibility to Salmonella enterica serovar Typhimurium

Intestinal microbiota comprise microbial communities that reside in the gastrointestinal tract and are critical to normal host physiology. Understanding the microbiota’s role in host response to invading pathogens will further expand our knowledge of host-microbe interactions, as well as foster advances in the design of novel therapeutic and prophylactic methods. In this dissertation I used clinically relevant doses of antibiotics to disturb the intestinal microbiota balance in a murine infection model. Pre-infection perturbations in the microbiota with two antibiotics resulted in increased mouse susceptibility to Salmonella enterica serovar Typhimurium intestinal colonization, greater post-infection alterations in the microbiota, and more severe intestinal pathology. This demonstrates the importance of a balanced microbiota community in host response to an enteric pathogen. This infection model also allowed further characterization of the host-pathogen-microbiota interactions during enteric salmonellosis. It was shown that in the presence of high numbers of indigenous microbes S. Typhimurium deficient in Salmonella pathogenicity island 2 (SPI2) is unable to trigger intestinal inflammation, while a SPI1 mutant strain promotes late typhlitis. Additionally, it was demonstrated that pathogen-induced intestinal inflammation does not always translate into extensive alterations to the host microbiota, as inflammation during a SPI1 mutant infection did not promote the same changes in host microbiota composition and numbers as inflammation induced by wild-type S. Typhimurium. Differential neutrophil recruitment by the three S. Typhimurium strains was implicated as one possible agent of microbiota perturbations. A thorough understanding of the tripartite host-microbiota-pathogen relationship in the progression of the enteric infections is needed to fully appreciate the disease process, as well as to suggest new avenues through which to interfere with the infection progression. These studies enhance our understanding of the microbiota’s role in the progression of S. Typhimurium infection and the effects of inflammation upon the microbiota, thus broadening our knowledge of S. Typhimurium pathogenesis and associated host response.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat