title: Dynamic Interactions of a Conserved Enterotoxigenic Escherichia coli Adhesin with Intestinal Mucins Govern Epithelium Engagement and Toxin Delivery.
abstract: At present, there is no vaccine for enterotoxigenic Escherichia coli (ETEC), an important cause of diarrheal illness. Nevertheless, recent microbial pathogenesis studies have identified a number of molecules produced by ETEC that contribute to its virulence and are novel antigenic targets to complement canonical vaccine approaches. EtpA is a secreted two-partner adhesin that is conserved within the ETEC pathovar. EtpA interacts with the tips of ETEC flagella to promote bacterial adhesion, toxin delivery, and intestinal colonization by forming molecular bridges between the bacteria and the epithelial surface. However, the nature of EtpA interactions with the intestinal epithelium remains poorly defined. Here, we demonstrate that EtpA interacts with glycans presented by transmembrane and secreted intestinal mucins at epithelial surfaces to facilitate pathogen-host interactions that culminate in toxin delivery. Moreover, we found that a major effector molecule of ETEC, the heat-labile enterotoxin (LT), may enhance these interactions by stimulating the production of the gel-forming mucin MUC2. Our studies suggest, however, that EtpA participates in complex and dynamic interactions between ETEC and the gastrointestinal mucosae in which host glycoproteins promote bacterial attachment while simultaneously limiting the epithelial engagement required for effective toxin delivery. Collectively, these data provide additional insight into the intricate nature of ETEC interactions with the intestinal epithelium that have potential implications for rational approaches to vaccine design.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Pardeep
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: F Matthew
authors.initials: FM
authors.lastname: Kuhlmann
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Kirandeep
authors.initials: K
authors.lastname: Bhullar
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Hyungjun
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Vallance
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Xia
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Luo
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, Missouri, USA jflecken@wustl.edu.|Microbial Pathogenesis Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, Missouri, USA.|Medicine Service, Veterans Affairs Medical Center, St. Louis, Missouri, USA.
authors.forename: James M
authors.identifier: http://orcid.org/0000-0002-1148-697X
authors.initials: JM
authors.lastname: Fleckenstein
mesh_terms: D000116:Acetylgalactosamine / Q000378:metabolism; D018829:Adhesins, Bacterial / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D054307:Enterotoxigenic Escherichia coli / Q000235:genetics / Q000502:physiology*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000382:microbiology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055262:Mucin-2 / Q000235:genetics / Q000378:metabolism; D009077:Mucins / Q000378:metabolism*; D034622:RNA Interference
chemical_list: D018829:Adhesins, Bacterial; D029968:Escherichia coli Proteins; C510011:EtpA protein, E coli; D008562:Membrane Glycoproteins; C524626:Muc2 protein, mouse; D055262:Mucin-2; D009077:Mucins; D000116:Acetylgalactosamine