Exploring the pathogen-commensal continuum: Cell wall auxotrophic bacteria in gnotobiotic mice

Cuenca Vera, Miguelangel (2016). Exploring the pathogen-commensal continuum: Cell wall auxotrophic bacteria in gnotobiotic mice. (Dissertation, University of Bern, Faculty of Medicine, Graduate School for Cellular and Biomedical Sciences)

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The intestinal tract of all known vertebrate animals is colonized with a high density of bacteria, forming host-specific communities. These communities are usually composed of a broad range of different species that have co-evolved with the host, to form very close and beneficial. In this thesis we developed a new tool for the study of host-microbiota interactions, based on the use of a proliferation controlled commensal E. coli strain and germ-free mice. This strain, contained a severe cell wall synthesis defect leading to the inability of proliferate without external supplementation. To guarantee the tightness of our system and its similarity to the wild type strain, we tested extensively the strain properties even under extreme cell wall starvation. This tool was further adapted to Salmonella enterica Typhimurium allowing us to simulate artificially the first six hours of a natural Salmonella infection, without the actual induction of disease. Our ability of simulating the early phase of an infection led to recognition of crucial in vivo bacterial adaptations, induced by the adaptive immunity, which led to the shift from pathogenic to commensal behavior in several Salmonella strains. The mechanism of this behavioral shift was explored, leading to the recognition of a Salmonella O-antigen shift, specific IgA induction and, exclusion of a pathogenic strain combined in to protection against disease when exposed to wild type Salmonella enterica. The additive effect of the discovered mechanisms was able to only partly explain the observed behavior, suggesting that other mechanisms remain to be uncovered to fully explain the behavioral shift.

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