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dc.contributor.authorRajan, Anubama
Robertson, Matthew J.
Carter, Hannah E.
Poole, Nina M.
Clark, Justin R.
Green, Sabrina I.
Criss, Zachary K.
Zhao, Boyang
Karandikar, Umesh
Xing, Yikun
Margalef-Català, Mar
Jain, Nikhil
Wilson, Reid L.
Bai, Fan
Hyser, Joseph M.
Petrosino, Joseph
Shroyer, Noah F.
Blutt, Sarah E.
Coarfa, Cristian
Song, Xuezheng
Prasad, BV Venkataram
Amieva, Manuel R.
Grande-Allen, Jane
Estes, Mary K.
Okhuysen, Pablo C.
Maresso, Anthony W.
dc.date.accessioned 2020-10-23T20:23:13Z
dc.date.available 2020-10-23T20:23:13Z
dc.date.issued 2020
dc.identifier.citation Rajan, Anubama, Robertson, Matthew J., Carter, Hannah E., et al.. "Enteroaggregative E. coli Adherence to Human Heparan Sulfate Proteoglycans Drives Segment and Host Specific Responses to Infection." PLOS Pathogens, 16, no. 9 (2020) Public Library of Science: https://doi.org/10.1371/journal.ppat.1008851.
dc.identifier.urihttps://hdl.handle.net/1911/109448
dc.description.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.
dc.language.iso eng
dc.publisher Public Library of Science
dc.rights 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.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.title Enteroaggregative E. coli Adherence to Human Heparan Sulfate Proteoglycans Drives Segment and Host Specific Responses to Infection
dc.type Journal article
dc.citation.journalTitle PLOS Pathogens
dc.subject.keywordGene expression
Colon
Duodenum
Escherichia coli infections
Gastrointestinal tract
Ileum
Mucin
Mucus
dc.citation.volumeNumber 16
dc.citation.issueNumber 9
dc.type.dcmi Text
dc.identifier.doihttps://doi.org/10.1371/journal.ppat.1008851
dc.type.publication publisher version
dc.citation.articleNumber e1008851


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