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How the enteric pathogen Shigella invades and destroys the gut: from molecular study to mechanobiology
Par Nathalie Sauvonnet (Pasteur)
Le 19 Mars 2019 à 11h00 - Salle de séminaires 5ème étage, Tour 32-33


Shigella is an enteroinvasive bacterium that induces human bacillary dysentery. The delivery of 30 bacterial effectors inside host cells allows the bacteria to invade colon epithelial cells, lyse the membrane of its vacuole, replicate and move into adjacent cells, subverting cellular and immune functions. Our recent work shows that Shigella flexneri blocks three main intracellular trafficking pathways of its host cell: the Golgi-mediated secretion, the recycling pathway and the endocytosis processes. Altogether, Shigella invasion freeze the exchange from the plasma membrane of its host cell. As a consequence Shigella disorganizes the epithelial cell polarity, disturbs epithelial barrier integrity, and enhances the pathogen capacity to penetrate into the colonic tissue in vivo. Next, we examined how this pathogen devoid of any adhesin or flagellum can reach the colonic tissue and invade it very efficiently. The gut continuously imposes two main physical forces on a colonizing pathogen, shear stress, induced by the intestinal flow, and stretching induced by the underlying muscle layer and resulting in the peristalsis, that may overcome the infectivity of pathogens. To investigate the role of mechanical forces of the intestine during Shigella infection, we used organ-on-a-chip, a microfluidic device allowing at recapitulating a 3D monolayer of epithelial cells under physical forces. Using this device, we observed a highly efficient Shigella invasion and tissue destruction even at very low bacterial loads, in contrast to the infection of polarized cells cultured in a 2D-monolayer. By modulating the flow rate and stretching conditions, we observed that both the 3D topology of the monolayer and the peristaltic motion greatly enhance the invasion and the destruction of the epithelial barrier. Thus the use of gut-on-a-chip technology revealed the important roles played by the architecture and the mechanical forces of the gut tissue for S. flexneri invasion.