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

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dc.citation.articleNumbere1008851en_US
dc.citation.issueNumber9en_US
dc.citation.journalTitlePLOS Pathogensen_US
dc.citation.volumeNumber16en_US
dc.contributor.authorRajan, Anubamaen_US
dc.contributor.authorRobertson, Matthew J.en_US
dc.contributor.authorCarter, Hannah E.en_US
dc.contributor.authorPoole, Nina M.en_US
dc.contributor.authorClark, Justin R.en_US
dc.contributor.authorGreen, Sabrina I.en_US
dc.contributor.authorCriss, Zachary K.en_US
dc.contributor.authorZhao, Boyangen_US
dc.contributor.authorKarandikar, Umeshen_US
dc.contributor.authorXing, Yikunen_US
dc.contributor.authorMargalef-Català, Maren_US
dc.contributor.authorJain, Nikhilen_US
dc.contributor.authorWilson, Reid L.en_US
dc.contributor.authorBai, Fanen_US
dc.contributor.authorHyser, Joseph M.en_US
dc.contributor.authorPetrosino, Josephen_US
dc.contributor.authorShroyer, Noah F.en_US
dc.contributor.authorBlutt, Sarah E.en_US
dc.contributor.authorCoarfa, Cristianen_US
dc.contributor.authorSong, Xuezhengen_US
dc.contributor.authorPrasad, BV Venkataramen_US
dc.contributor.authorAmieva, Manuel R.en_US
dc.contributor.authorGrande-Allen, Janeen_US
dc.contributor.authorEstes, Mary K.en_US
dc.contributor.authorOkhuysen, Pablo C.en_US
dc.contributor.authorMaresso, Anthony W.en_US
dc.contributor.orgBioengineeringen_US
dc.date.accessioned2020-10-23T20:23:13Zen_US
dc.date.available2020-10-23T20:23:13Zen_US
dc.date.issued2020en_US
dc.description.abstractEnteroaggregative 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.en_US
dc.identifier.citationRajan, 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." <i>PLOS Pathogens,</i> 16, no. 9 (2020) Public Library of Science: https://doi.org/10.1371/journal.ppat.1008851.en_US
dc.identifier.doihttps://doi.org/10.1371/journal.ppat.1008851en_US
dc.identifier.urihttps://hdl.handle.net/1911/109448en_US
dc.language.isoengen_US
dc.publisherPublic Library of Scienceen_US
dc.rightsThis 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.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subject.keywordGene expressionen_US
dc.subject.keywordColonen_US
dc.subject.keywordDuodenumen_US
dc.subject.keywordEscherichia coli infectionsen_US
dc.subject.keywordGastrointestinal tracten_US
dc.subject.keywordIleumen_US
dc.subject.keywordMucinen_US
dc.subject.keywordMucusen_US
dc.titleEnteroaggregative E. coli Adherence to Human Heparan Sulfate Proteoglycans Drives Segment and Host Specific Responses to Infectionen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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