PMID- 28531220 OWN - NLM STAT- MEDLINE DCOM- 20170710 LR - 20230804 IS - 1935-2735 (Electronic) IS - 1935-2727 (Print) IS - 1935-2727 (Linking) VI - 11 IP - 5 DP - 2017 May TI - Highly conserved type 1 pili promote enterotoxigenic E. coli pathogen-host interactions. PG - e0005586 LID - 10.1371/journal.pntd.0005586 [doi] LID - e0005586 AB - Enterotoxigenic Escherichia coli (ETEC), defined by their elaboration of heat-labile (LT) and/or heat-stable (ST) enterotoxins, are a common cause of diarrheal illness in developing countries. Efficient delivery of these toxins requires ETEC to engage target host enterocytes. This engagement is accomplished using a variety of pathovar-specific and conserved E. coli adhesin molecules as well as plasmid encoded colonization factors. Some of these adhesins undergo significant transcriptional modulation as ETEC encounter intestinal epithelia, perhaps suggesting that they cooperatively facilitate interaction with the host. Among genes significantly upregulated on cell contact are those encoding type 1 pili. We therefore investigated the role played by these pili in facilitating ETEC adhesion, and toxin delivery to model intestinal epithelia. We demonstrate that type 1 pili, encoded in the E. coli core genome, play an essential role in ETEC virulence, acting in concert with plasmid-encoded pathovar specific colonization factor (CF) fimbriae to promote optimal bacterial adhesion to cultured intestinal epithelium (CIE) and to epithelial monolayers differentiated from human small intestinal stem cells. Type 1 pili are tipped with the FimH adhesin which recognizes mannose with stereochemical specificity. Thus, enhanced production of highly mannosylated proteins on intestinal epithelia promoted FimH-mediated ETEC adhesion, while conversely, interruption of FimH lectin-epithelial interactions with soluble mannose, anti-FimH antibodies or mutagenesis of fimH effectively blocked ETEC adhesion. Moreover, fimH mutants were significantly impaired in delivery of both heat-stable and heat-labile toxins to the target epithelial cells in vitro, and these mutants were substantially less virulent in rabbit ileal loop assays, a classical model of ETEC pathogenesis. Collectively, our data suggest that these highly conserved pili play an essential role in virulence of these diverse pathogens. FAU - Sheikh, Alaullah AU - Sheikh A AUID- ORCID: 0000-0002-2972-6978 AD - Molecular Microbiology and Microbial Pathogenesis Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, Saint Louis, Missouri, United States of America. FAU - Rashu, Rasheduzzaman AU - Rashu R AD - Infectious Diseases Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddrb), Mohakhali, Dhaka, Bangladesh. FAU - Begum, Yasmin Ara AU - Begum YA AD - Infectious Diseases Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddrb), Mohakhali, Dhaka, Bangladesh. FAU - Kuhlman, F Matthew AU - Kuhlman FM AUID- ORCID: 0000-0003-1085-0589 AD - Division of Infectious Disease, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America. FAU - Ciorba, Matthew A AU - Ciorba MA AD - Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America. FAU - Hultgren, Scott J AU - Hultgren SJ AD - Department of Molecular Microbiology, Washington University in Saint Louis, Saint Louis, Missouri, United States of America. AD - Center for Women's Infectious Disease Research (CWIDR), Washington University in Saint Louis, Saint Louis, Missouri, United States of America. FAU - Qadri, Firdausi AU - Qadri F AD - Infectious Diseases Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddrb), Mohakhali, Dhaka, Bangladesh. FAU - Fleckenstein, James M AU - Fleckenstein JM AUID- ORCID: 0000-0002-1148-697X AD - Molecular Microbiology and Microbial Pathogenesis Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, Saint Louis, Missouri, United States of America. AD - Division of Infectious Disease, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America. AD - Medicine Service, Veterans Affairs Medical Center, Saint Louis, Missouri, United States of America. LA - eng GR - R37 AI048689/AI/NIAID NIH HHS/United States GR - R01 AI089894/AI/NIAID NIH HHS/United States GR - R01 AI126887/AI/NIAID NIH HHS/United States GR - R01 DK109384/DK/NIDDK NIH HHS/United States GR - P30 DK052574/DK/NIDDK NIH HHS/United States GR - R01 AI048689/AI/NIAID NIH HHS/United States GR - I01 BX001469/BX/BLRD VA/United States PT - Journal Article DEP - 20170522 PL - United States TA - PLoS Negl Trop Dis JT - PLoS neglected tropical diseases JID - 101291488 RN - 0 (Adhesins, Bacterial) RN - 0 (Bacterial Toxins) RN - 0 (Enterotoxins) RN - 0 (Escherichia coli Proteins) RN - 0 (heat stable toxin (E coli)) RN - D9K3SN2LNY (heat-labile enterotoxin, E coli) SB - IM MH - Adhesins, Bacterial/*metabolism MH - Bacterial Adhesion MH - Bacterial Toxins/metabolism MH - Caco-2 Cells MH - Enterotoxigenic Escherichia coli/*pathogenicity MH - Enterotoxins/metabolism MH - Epithelial Cells/*microbiology MH - Escherichia coli Proteins/metabolism MH - Fimbriae, Bacterial/*metabolism MH - *Host-Pathogen Interactions MH - Humans MH - Protein Transport PMC - PMC5456409 COIS- I have read the journal's policy and the authors of this manuscript have the following competing interests: SJH has an ownership interest in Fimbrion Therapeutics. EDAT- 2017/05/23 06:00 MHDA- 2017/07/14 06:00 PMCR- 2017/05/22 CRDT- 2017/05/23 06:00 PHST- 2017/03/08 00:00 [received] PHST- 2017/04/21 00:00 [accepted] PHST- 2017/06/02 00:00 [revised] PHST- 2017/05/23 06:00 [pubmed] PHST- 2017/07/14 06:00 [medline] PHST- 2017/05/23 06:00 [entrez] PHST- 2017/05/22 00:00 [pmc-release] AID - PNTD-D-17-00340 [pii] AID - 10.1371/journal.pntd.0005586 [doi] PST - epublish SO - PLoS Negl Trop Dis. 2017 May 22;11(5):e0005586. doi: 10.1371/journal.pntd.0005586. eCollection 2017 May.