Enteroaggregative E. coli Adherence to Human Heparan Sulfate Proteoglycans Drives Segment and Host Specific Responses to Infection.
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 pathoty...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2020-09-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1008851 |
| _version_ | 1797900542711693312 |
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| author | Anubama Rajan Matthew J Robertson Hannah E Carter Nina M Poole Justin R Clark Sabrina I Green Zachary K Criss Boyang Zhao Umesh Karandikar Yikun Xing Mar Margalef-Català Nikhil Jain Reid L Wilson Fan Bai Joseph M Hyser Joseph Petrosino Noah F Shroyer Sarah E Blutt Cristian Coarfa Xuezheng Song Bv Venkataram Prasad Manuel R Amieva Jane Grande-Allen Mary K Estes Pablo C Okhuysen Anthony W Maresso |
| author_facet | Anubama Rajan Matthew J Robertson Hannah E Carter Nina M Poole Justin R Clark Sabrina I Green Zachary K Criss Boyang Zhao Umesh Karandikar Yikun Xing Mar Margalef-Català Nikhil Jain Reid L Wilson Fan Bai Joseph M Hyser Joseph Petrosino Noah F Shroyer Sarah E Blutt Cristian Coarfa Xuezheng Song Bv Venkataram Prasad Manuel R Amieva Jane Grande-Allen Mary K Estes Pablo C Okhuysen Anthony W Maresso |
| author_sort | Anubama Rajan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T08:47:36Z |
| format | Article |
| id | doaj.art-15fac49c9e804f7ab44e6b10cab5b95e |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-04-10T08:47:36Z |
| publishDate | 2020-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-15fac49c9e804f7ab44e6b10cab5b95e2023-02-22T05:31:02ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742020-09-01169e100885110.1371/journal.ppat.1008851Enteroaggregative E. coli Adherence to Human Heparan Sulfate Proteoglycans Drives Segment and Host Specific Responses to Infection.Anubama RajanMatthew J RobertsonHannah E CarterNina M PooleJustin R ClarkSabrina I GreenZachary K CrissBoyang ZhaoUmesh KarandikarYikun XingMar Margalef-CatalàNikhil JainReid L WilsonFan BaiJoseph M HyserJoseph PetrosinoNoah F ShroyerSarah E BluttCristian CoarfaXuezheng SongBv Venkataram PrasadManuel R AmievaJane Grande-AllenMary K EstesPablo C OkhuysenAnthony W MaressoEnteroaggregative 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.https://doi.org/10.1371/journal.ppat.1008851 |
| spellingShingle | Anubama Rajan Matthew J Robertson Hannah E Carter Nina M Poole Justin R Clark Sabrina I Green Zachary K Criss Boyang Zhao Umesh Karandikar Yikun Xing Mar Margalef-Català Nikhil Jain Reid L Wilson Fan Bai Joseph M Hyser Joseph Petrosino Noah F Shroyer Sarah E Blutt Cristian Coarfa Xuezheng Song Bv Venkataram Prasad Manuel R Amieva Jane Grande-Allen Mary K Estes Pablo C Okhuysen Anthony W Maresso Enteroaggregative E. coli Adherence to Human Heparan Sulfate Proteoglycans Drives Segment and Host Specific Responses to Infection. PLoS Pathogens |
| title | Enteroaggregative E. coli Adherence to Human Heparan Sulfate Proteoglycans Drives Segment and Host Specific Responses to Infection. |
| title_full | Enteroaggregative E. coli Adherence to Human Heparan Sulfate Proteoglycans Drives Segment and Host Specific Responses to Infection. |
| title_fullStr | Enteroaggregative E. coli Adherence to Human Heparan Sulfate Proteoglycans Drives Segment and Host Specific Responses to Infection. |
| title_full_unstemmed | Enteroaggregative E. coli Adherence to Human Heparan Sulfate Proteoglycans Drives Segment and Host Specific Responses to Infection. |
| title_short | Enteroaggregative E. coli Adherence to Human Heparan Sulfate Proteoglycans Drives Segment and Host Specific Responses to Infection. |
| title_sort | enteroaggregative e coli adherence to human heparan sulfate proteoglycans drives segment and host specific responses to infection |
| url | https://doi.org/10.1371/journal.ppat.1008851 |
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