The in vivo response of the intestinal epithelium to bacterial infection

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Salmonella is able to invade non-phagocytic intestinal epithelial cells followed by intracellular proliferation and transepithelial migration. The conservation of the responsible molecular effector molecules in human Salmonella isolates suggests a critical contribution of this step in the pathogenesis of infection. Although extensively studied in vitro, the interaction of Salmonella with the intestinal epithelium and the epithelial innate immune response has remained ill defined in vivo. Immortalized epithelial cell lines do not reflect the complex cell composition, functional differentiation, anatomical organisation and luminal exposure of the epithelium in vivo. Our newly established oral Salmonella infection model in neonate mice for the first time opens the possibility to investigate the invasion-induced epithelial stimulation in vivo in a suitable host amenable to genetic modification (Zhang et al., 2014). This in vivo model is complemented by the use of ex vivo derived stem cell organoids to (i) characterize the Salmonella-induced epithelial innate immune signaling, (ii) evaluate downstream effects of infection-induced epithelial innate immune stimulation and (iii) analyze bacterial virulence factors and their interference with epithelial innate immune signaling. We expect that the proposed experiments provide a better understanding of the early phase of the mucosal host response to infection, i.e. the interaction between the intestinal epithelium and Salmonella in vivo. We hope that a better understanding will facilitate the development of new strategies to prevent or restrict disease at an early stage of the infection and identify age-dependent factors underlying the susceptibility of the neonate host to invasive Salmonella infection.