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Diarrhea is a host response to enteric pathogens, but its impact on pathogenesis remains poorly defined. By infecting mice with the attaching and effacing bacteria
we defined the mechanisms and contributions of diarrhea and intestinal barrier loss to host defense. Increased permeability occurred within 2 days of infection and coincided with IL-22-dependent upregulation of the epithelial tight junction protein claudin-2. Permeability increases were limited to small molecules, as expected for the paracellular water and Na
channel formed by claudin-2. Relative to wildtype, claudin-2-deficient mice experienced severe disease, including increased mucosal colonization by
, prolonged pathogen shedding, exaggerated cytokine responses, and greater tissue injury. Conversely, transgenic claudin-2 overexpression reduced disease severity. Chemically-induced osmotic diarrhea reduced colitis severity and
burden in claudin-2 deficient, but not transgenic, mice, demonstrating that claudin-2-mediated protection is the result of enhanced water efflux. Thus, IL-22-induced claudin-2 upregulation drives diarrhea and pathogen clearance.
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Right: In the absence of claudin-2, clearance of
(red) is impaired and bacteria are able to invade the normally-protected colonic crypt lumen. F-actin (green) and DNA (blue).