Abstract
The potential immunomodulatory role of microRNAs in small intestine of patients with acute watery diarrhea caused by Vibrio cholerae O1 or enterotoxigenic Escherichia coli (ETEC) infection was investigated. Duodenal biopsies were obtained from study-participants at the acute (day 2) and convalescent (day 21) stages of disease, and from healthy individuals. Levels of miR-146a, miR-155 and miR-375 and target gene (IRAK1, TRAF6, CARD10) and 11 cytokine mRNAs were determined by qRT-PCR. The cellular source of microRNAs in biopsies was analyzed by in situ hybridization. The ability of V. cholerae bacteria and their secreted products to cause changes in microRNA- and mRNA levels in polarized tight monolayers of intestinal epithelial cells was investigated. miR-146a and miR-155 were expressed at significantly elevated levels at acute stage of V. cholerae infection and declined to normal at convalescent stage (P<0.009 versus controls; P = 0.03 versus convalescent stage, pairwise). Both microRNAs were mainly expressed in the epithelium. Only marginal down-regulation of target genes IRAK1 and CARD10 was seen and a weak cytokine-profile was identified in the acute infected mucosa. No elevation of microRNA levels was seen in ETEC infection. Challenge of tight monolayers with the wild type V. cholerae O1 strain C6706 and clinical isolates from two study-participants, caused significant increase in miR-155 and miR-146a by the strain C6706 (P<0.01). One clinical isolate caused reduction in IRAK1 levels (P<0.05) and none of the strains induced inflammatory cytokines. In contrast, secreted factors from these strains caused markedly increased levels of IL-8, IL-1β, and CARD10 (P<0.001), without inducing microRNA expression. Thus, miR-146a and miR-155 are expressed in the duodenal epithelium at the acute stage of cholera. The inducer is probably the V. cholerae bacterium. By inducing microRNAs the bacterium can limit the innate immune response of the host, including inflammation evoked by its own secreted factors, thereby decreasing the risk of being eliminated.
Highlights
Vibrio cholerae O1 and Enterotoxigenic Escherichia coli (ETEC) are the predominant causes of acute dehydrating diarrhea in developing countries such as Bangladesh where a large proportion of cases requiring hospitalization are reported [1,2,3,4]
To investigate whether the miRNAs miR-146a, miR-155 and miR-375 are induced by V. cholerae O1 and ETEC infection, paired duodenal biopsies were collected from six V. cholerae O1 and four ETEC infected patients at acute stage and convalescent stage of disease and compared to single biopsies of five healthy controls
In the present study we identified the increased expression of miR-146a and miR-155 in a major population of epithelial cells and in scattered cells, presumably immune cells, in the lamina propria of duodenal mucosa in patients at the acute stage of V. cholerae O1 infection, while these microRNAs were not induced by ETEC infection
Summary
Vibrio cholerae O1 and Enterotoxigenic Escherichia coli (ETEC) are the predominant causes of acute dehydrating diarrhea in developing countries such as Bangladesh where a large proportion of cases requiring hospitalization are reported [1,2,3,4]. Both pathogens are non-invasive and colonize the small intestine. Two microRNAs shown to be highly involved in the regulation of the acute inflammatory response after pathogen recognition through Tolllike receptors (TLRs) are miR-146a and miR-155 [17]. Caspase recruitment domain family member 10 (CARD10) was identified as a target mRNA for miR146a upon NFκ B activation of human retinal endothelial cells [21]
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