Abstract
Gastrointestinal infections with EHEC and EPEC are responsible for outbreaks of diarrheal diseases and represent a global health problem. Innate first-line-defense mechanisms such as production of mucus and antimicrobial peptides by intestinal epithelial cells are of utmost importance for host control of gastrointestinal infections. For the first time, we directly demonstrate a critical role for Stat3 activation in intestinal epithelial cells upon infection of mice with Citrobacter rodentium – a murine pathogen that mimics human infections with attaching and effacing Escherichia coli. C. rodentium induced transcription of IL-6 and IL-22 in gut samples of mice and was associated with activation of the transcription factor Stat3 in intestinal epithelial cells. C. rodentium infection induced expression of several antimicrobial peptides such as RegIIIγ and Pla2g2a in the intestine which was critically dependent on Stat3 activation. Consequently, mice with specific deletion of Stat3 in intestinal epithelial cells showed increased susceptibility to C. rodentium infection as indicated by high bacterial load, severe gut inflammation, pronounced intestinal epithelial cell death and dissemination of bacteria to distant organs. Together, our data implicate an essential role for Stat3 activation in intestinal epithelial cells during C. rodentium infection. Stat3 concerts the host response to bacterial infection by controlling bacterial growth and suppression of apoptosis to maintain intestinal epithelial barrier function.
Highlights
Bacterial infections of the gastrointestinal tract are a frequent cause of diarrhea followed by dehydration and are estimated to cause 2.5 million deaths per year, especially in underdeveloped countries [1]
Our finding is in line with recent data published by Zheng et al [14], showing that IL-22 was strongly increased after C. rodentium infection
IL-22 has been found to play a major role in infections with the enterohaemorrhagic E. coli (EHEC)/enteropathogenic E. coli (EPEC) like pathogen C. rodentium in mice [14]
Summary
Bacterial infections of the gastrointestinal tract are a frequent cause of diarrhea followed by dehydration and are estimated to cause 2.5 million deaths per year, especially in underdeveloped countries [1]. Among the diarrhea-inducing bacteria, pathogenic Escherichia coli such as enteropathogenic E. coli (EPEC) and enterohaemorrhagic E. coli (EHEC) frequently cause outbreaks of diarrheal diseases [2, 3]. The largest outbreak of EHEC infection ever seen in Europe occurred in Germany in spring 2011: more than 2,900 cases of acute gastroenteritis, more than.
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