Bacterial and host factors governing enterocyte exit of Salmonella

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Hallmark of the pathogenesis of Salmonella is the ability to penetrate the intact intestinal epithelial barrier, reach the underlying lamina propria and evoke an inflammatory response. Penetration of the epithelial barrier requires invasion of non-phagocytic cells, intracellular survival, apical to basolateral transmigration and cell exit. Whereas cell invasion and intracellular survival have been extensively investigated during the last decades, the process the Salmonella transmigration and exit from epithelial cells has not obtained much attention. Based on our previous work, here we plan to functionally characterize the basolateral and apical enterocyte exit, screen for and analyze bacterial factors influencing enterocyte exit, and investigate apical enterocyte exit and its role in vivo in host transmission. To achieve these goals, life imaging and advanced electron microscopy, transposon mutagenesis and an iterative co-culture screen to identify genes promoting cell exit, targeted bacterial mutagenesis, and genetic fate mapping will be employed in combination with an in vitro co-culture model of polarized intestinal epithelial m-ICcl2 cells grown on transwell inserts, intestinal epithelial stem cell organoids and an established neonatal mouse infection model. The results are expected to significantly broaden our understanding of the intricate host-microbe interaction during the early course of the infection and may provide molecular targets for future preventive or therapeutic strategies.