Enteroaggregative E.coliAdherence to Human Heparan Sulfate Proteoglycans Drives Segment and Host Specific Responses to Infection

• Type of Material: Article
• Authors: Anubama Rajan, Baylor College of Medicine; Matthew J. Robertson, Baylor College of Medicine; Hannah E. Carter, Baylor College of Medicine; Nina M. Poole, Baylor College of Medicine; Justin R. Clark, Baylor College of Medicine; Sabrina I. Green, Baylor College of Medicine; Zachary K. Criss, Baylor College of Medicine; Boyang Zhao, Baylor College of Medicine; Umesh Karandikar, Baylor College of Medicine; Yikun Xing, Baylor College of Medicine; Mar Margalef-Catala, Stanford University; Nihil Jain, Baylor College of Medicine; Reid L. Wilson, Rice University; Fan Bai, Emory University; Joseph M. Hyser, Baylor College of Medicine; Joseph Petrosino, Baylor College of Medicine; Noah F. Shroyer, Baylor College of Medicine; Sarah E. Blutt, Baylor College of Medicine; Cristian Coarfa, Baylor College of Medicine; Xuezheng Song, Emory University; B.V. Venkataram Prasad, Baylor College of Medicine; Manuel R. Amieva, Stanford University; Jane Grande-Allen, Rice University; Mary K. Estes, Baylor College of Medicine; Pablo C. Okhuysen, University of Texas MD Anderson Cancer Center; Anthony W. Maresso, Baylor College of Medicine
• Language: English
• Date: 2020-09-01
• Publisher: PUBLIC LIBRARY SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2020 Rajan et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1008851
• Title of Journal or Parent Work: PLOS PATHOGENS
• Volume: 16
• Issue: 9
• Start Page: e1008851
• End Page: e1008851
• Grant/Funding Information: These studies were supported in part by grant U19 AI11497 that is as part of the U19 program (Novel Alternative Models of Enteric Diseases–NAMSED) from the National Institutes of Health assigned to MKE and AWM and from seed funds NAMSED institutional 1383006110 to AWM from Baylor College of Medicine. This study was partially supported by NIH P30 shared resource grant CA125123, NIEHS grants 1P30ES030285 and 1P42ES0327725 (MJR,CC) and by The Cancer Prevention Institute of Texas (CPRIT) RP170005. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors sincerely apologize for any work left uncited do to journal space constraints.
• Keywords: Science & Technology; GUT MICROBIOTA; DIARRHEAGENIC ESCHERICHIA-COLI; ADHERENCE; IN-VITRO; PERSISTENT DIARRHEA; EX-VIVO MODEL; 2 MUCUS LAYERS; Life Sciences & Biomedicine; EXPRESSION ANALYSIS; TRAVELERS DIARRHEA; Parasitology; Virology; Microbiology; HUMAN INTESTINAL ENTEROIDS
• Research Categories: Biology, Virology; Biology, Microbiology; Biology, Parasitology

Abstract

Enteroaggregative Escherichia coli (EAEC) is a significant cause of acute and chronic diarrhea, foodborne outbreaks, infections of the immunocompromised, and growth stunting in children in developing nations. There is no vaccine and resistance to antibiotics is rising. Unlike related E. coli pathotypes that are often associated with acute bouts of infection, EAEC is associated with persistent diarrhea and subclinical long-term colonization. Several secreted virulence factors have been associated with EAEC pathogenesis and linked to disease in humans, less certain are the molecular drivers of adherence to the intestinal mucosa. We previously established human intestinal enteroids (HIEs) as a model system to study host-EAEC interactions and aggregative adherence fimbriae A (AafA) as a major driver of EAEC adherence to HIEs. Here, we report a large-scale assessment of the host response to EAEC adherence from all four segments of the intestine across at least three donor lines for five E. coli pathotypes. The data demonstrate that the host response in the duodenum is driven largely by the infecting pathotype, whereas the response in the colon diverges in a patient-specific manner. Major pathways altered in gene expression in each of the four enteroid segments differed dramatically, with responses observed for inflammation, apoptosis and an overwhelming response to different mucin genes. In particular, EAEC both associated with large mucus droplets and specific mucins at the epithelial surface, binding that was ameliorated when mucins were removed, a process dependent on AafA. Pan-screening for glycans for binding to purified AafA identified the human ligand as heparan sulfate proteoglycans (HSPGs). Removal of HSPG abrogated EAEC association with HIEs. These results may mean that the human intestine responds remarkably different to distinct pathobionts that is dependent on the both the individual and intestinal segment in question, and uncover a major role for surface heparan sulfate proteoglycans as tropism-driving factor in adherence and/or colonization.