Enteroaggregative E. coli Adherence to Human Heparan Sulfate Proteoglycans Drives Segment and Host Specific Responses to Infection.
Adhesins, Escherichia coli
/ genetics
Bacterial Adhesion
/ physiology
Escherichia coli
/ metabolism
Escherichia coli Infections
/ metabolism
Escherichia coli Proteins
/ metabolism
Fimbriae, Bacterial
/ metabolism
Heparan Sulfate Proteoglycans
/ metabolism
Humans
Intestinal Mucosa
/ metabolism
Virulence Factors
/ metabolism
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
21
05
2020
accepted:
01
08
2020
revised:
13
10
2020
pubmed:
29
9
2020
medline:
13
11
2020
entrez:
28
9
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32986782
doi: 10.1371/journal.ppat.1008851
pii: PPATHOGENS-D-20-01075
pmc: PMC7553275
doi:
Substances chimiques
Adhesins, Escherichia coli
0
Escherichia coli Proteins
0
Heparan Sulfate Proteoglycans
0
Virulence Factors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008851Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK118904
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI116497
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI055413
Pays : United States
Organisme : NIDDK NIH HHS
ID : F30 DK108541
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK115507
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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