Induction of immunomodulatory miR-146a and miR-155 in small intestinal epithelium of Vibrio cholerae infected patients at acute stage of cholera.
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.
Department of Clinical Microbiology, Immunology, Umeå University, Umeå, Sweden.
Aziz
A
Bitar
Department of Clinical Microbiology, Immunology, Umeå University, Umeå, Sweden.|Department of Molecular Biology, The Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden.
Rituparna
R
De
APC Microbiome Institute, University College Cork, Cork City, Ireland.
Silvia
S
Melgar
Department of Clinical Microbiology, Immunology, Umeå University, Umeå, Sweden.|Department of Molecular Biology, The Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden.
Kyaw Min
KM
Aung
UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.
Arman
A
Rahman
International Centre for Diarrheal Disease Research, Bangladesh, Dhaka, Bangladesh.
Firdausi
F
Qadri
Department of Molecular Biology, The Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden.
Sun Nyunt
SN
Wai
Department of Virology, Institute of Epidemiology Disease Control & Research (IEDCR), National Influenza Centre (NIC), Dhaka, Bangladesh.
Tahmina
T
Shirin
Department of Clinical Microbiology, Immunology, Umeå University, Umeå, Sweden.
Marie-Louise
http://orcid.org/0000-0001-6182-4423
ML
Hammarström
D000208:Acute Disease; D000328:Adult; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics; D002771:Cholera / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D056747:Immunomodulation; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism; D007421:Intestine, Small / Q000276:immunology* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics; D014734:Vibrio cholerae / Q000502:physiology*; D055815:Young Adult
D053468:CARD Signaling Adaptor Proteins; C430880:CARD10 protein, human; C542542:MIRN146 microRNA, human; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D048029:TNF Receptor-Associated Factor 6; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases