@article{5a19455001484168bd325c87b0e1c6fa,
title = "Enteroaggregative e. coli adherence to human heparan sulfate proteoglycans drives segment and host specific responses to infection",
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.",
author = "Anubama Rajan and Robertson, {Matthew J.} and Carter, {Hannah E.} and Poole, {Nina M.} and Clark, {Justin R.} and Green, {Sabrina I.} and Criss, {Zachary K.} and Boyang Zhao and Umesh Karandikar and Yikun Xing and Mar Margalef-Catal{\`a} and Nikhil Jain and Wilson, {Reid L.} and Fan Bai and Hyser, {Joseph M.} and Joseph Petrosino and Shroyer, {Noah F.} and Blutt, {Sarah E.} and Cristian Coarfa and Xuezheng Song and Prasad, {B. V.Venkataram} and Amieva, {Manuel R.} and Jane Grande-Allen and Estes, {Mary K.} and Okhuysen, {Pablo C.} and Maresso, {Anthony W.}",
note = "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. 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. Publisher Copyright: {\textcopyright} 2020 Rajan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
year = "2020",
month = sep,
doi = "10.1371/journal.ppat.1008851",
language = "English (US)",
volume = "16",
journal = "PLoS pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "9",
}