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Salmonella enterica serovar Typhimurium infection of the gallbladder : a novel in vivo epithelial cell infection model

University of British Columbia

The gallbladder has long been recognized as a site of infection during systemic salmonellosis; yet little is known regarding bacterial pathogenesis in this organ. My PhD research constitutes the first detailed characterization of a bacterial infection of the gallbladder, focusing on the local biology, pathology, and immunology of Salmonella infection. Using a murine model of acute typhoid fever, it was found that Salmonella in the gallbladder show a unique behavior, as they remained confined to gallbladder epithelial cells without translocating to the mucosa. Moreover, they replicated within these cells instead of phagocytes. These findings add yet another functional significance to the invasion phenotype in vivo, and together with the presence of high numbers of extracellular, luminal bacteria, put forward the concept that acute infection of the gallbladder may be important for later events in the bacterial life cycle. A murine model of persistent typhoid infection revealed that gallbladder colonization occurs intermittently during chronic infection and that colonization may result in pathological damage. The in vivo work described here validates some of the paradigms of Salmonella infection, but also shows that Salmonella accumulation in vivo does no exclusively occur in the canonical intra-macrophage niche. This research also established a new system for the study of Salmonella Typhimurium’s biology, and a way to probe the biological function of individual gene products in a meaningful in vivo infection model. The model was validated in a screen of Salmonella mutants of known virulence factors involved in intracellular survival and replication within host cells. Novel phenotypes were described within this more natural host:pathogen environment, which highlighted potentially new biological functions for several Salmonella genes. This is the first study of its kind, which reveals the usefulness of the in vivo gallbladder epithelial cell infection model. It is hoped that future studies using this system shall continue to impact the field of Salmonella pathogenesis.

Text

2010-11-16

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/29967

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/