Disruption of the epithelial barrier upon Shigella flexneri infection

Shigella is one of the most communicable bacterial pathogens and causes the disease shigellosis. Shigella invades the colonic mucosa from the basolateral surface, but how Shigella gets to the basolateral domain is incompletely understood. We have shown that S. flexneri alters the cell‐cell junction complex facilitating paracellular passage of the organism across the epithelial barrier. To understand the mechanism by which this bacterium alters the intestinal epithelial junctions, we focused on SepA, a bacterial protein associated with tissue invasion and destruction upon infection. To test the hypothesis that SepA is involved in altering the intestinal epithelial barrier function, polarized monolayers of human intestinal epithelia or xenotransplanted human intestine were infected with wild‐type S. flexneri or an isogenic SepA mutant strain. We found that absence of SepA lead to a less severe disturbance on the intestinal barrier, which correlate with not only a decrease in bacterial invasion, but also significant reduction of neutrophils transepithelial migration. Functionally, we found SepA to elicit cleavage of the intracellular domain of E‐cadherin, which we speculate contributes to the observed cell‐cell junction permeability, and in turns permits S. flexneri access to the basolateral domain to invade and trigger the intense inflammatory response, a hallmark of this disease. NIH