PMID- 34807735 OWN - NLM STAT- MEDLINE DCOM- 20220420 LR - 20231009 IS - 1098-5522 (Electronic) IS - 0019-9567 (Print) IS - 0019-9567 (Linking) VI - 90 IP - 2 DP - 2022 Feb 17 TI - Enterotoxigenic Escherichia coli Degrades the Host MUC2 Mucin Barrier To Facilitate Critical Pathogen-Enterocyte Interactions in Human Small Intestine. PG - e0057221 LID - 10.1128/IAI.00572-21 [doi] LID - e00572-21 AB - Enterotoxigenic Escherichia coli (ETEC) isolates are genetically diverse pathological variants of E. coli defined by the production of heat-labile (LT) and/or heat-stable (ST) toxins. ETEC strains are estimated to cause hundreds of millions of cases of diarrheal illness annually. However, it is not clear that all strains are equally equipped to cause disease, and asymptomatic colonization with ETEC is common in low- to middle-income regions lacking basic sanitation and clean water where ETEC are ubiquitous. Recent molecular epidemiology studies have revealed a significant association between strains that produce EatA, a secreted autotransporter protein, and the development of symptomatic infection. Here, we demonstrate that LT stimulates production of MUC2 mucin by goblet cells in human small intestine, enhancing the protective barrier between pathogens and enterocytes. In contrast, using explants of human small intestine as well as small intestinal enteroids, we show that EatA counters this host defense by engaging and degrading the MUC2 mucin barrier to promote bacterial access to target enterocytes and ultimately toxin delivery, suggesting that EatA plays a crucial role in the molecular pathogenesis of ETEC. These findings may inform novel approaches to prevention of acute diarrheal illness as well as the sequelae associated with ETEC and other pathogens that rely on EatA and similar proteases for efficient interaction with their human hosts. FAU - Sheikh, Alaullah AU - Sheikh A AUID- ORCID: 0000-0002-2972-6978 AD - Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, Missouri, USA. FAU - Wangdi, Tamding AU - Wangdi T AD - Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, Missouri, USA. FAU - Vickers, Tim J AU - Vickers TJ AD - Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, Missouri, USA. FAU - Aaron, Bailey AU - Aaron B AD - Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, Missouri, USA. FAU - Palmer, Margot AU - Palmer M AD - Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, Missouri, USA. FAU - Miller, Mark J AU - Miller MJ AD - Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, Missouri, USA. FAU - Kim, Seonyoung AU - Kim S AD - Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, Missouri, USA. FAU - Herring, Cassandra AU - Herring C AD - Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, Missouri, USA. FAU - Simoes, Rita AU - Simoes R AD - Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, Missouri, USA. FAU - Crainic, Jennifer A AU - Crainic JA AD - Center for Cancer Research, Chemical Biology Laboratory, National Cancer Institutegrid.48336.3a, Fredrick, Maryland, USA. FAU - Gildersleeve, Jeffrey C AU - Gildersleeve JC AD - Center for Cancer Research, Chemical Biology Laboratory, National Cancer Institutegrid.48336.3a, Fredrick, Maryland, USA. FAU - van der Post, Sjoerd AU - van der Post S AD - Department of Medical Biochemistry and Cell Biology, University of Gothenburggrid.8761.8, Gothenburg, Sweden. FAU - Hansson, Gunnar C AU - Hansson GC AD - Department of Medical Biochemistry and Cell Biology, University of Gothenburggrid.8761.8, Gothenburg, Sweden. FAU - Fleckenstein, James M AU - Fleckenstein JM AUID- ORCID: 0000-0002-1148-697X AD - Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, Missouri, USA. AD - Medicine Service, Veterans Affairs Medical Center, Saint Louis, Missouri, USA. LA - eng GR - I01 BX001469/BX/BLRD VA/United States GR - R01 AI089894/AI/NIAID NIH HHS/United States GR - P30 AR073752/AR/NIAMS NIH HHS/United States GR - R01 AI126887/AI/NIAID NIH HHS/United States GR - R01 AI077600/AI/NIAID NIH HHS/United States GR - UL1 TR002345/TR/NCATS NIH HHS/United States GR - I01 BX004825/BX/BLRD VA/United States GR - T32 AI007172/AI/NIAID NIH HHS/United States GR - U01 AI095473/AI/NIAID NIH HHS/United States GR - P30 DK052574/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20211122 PL - United States TA - Infect Immun JT - Infection and immunity JID - 0246127 RN - 0 (Bacterial Toxins) RN - 0 (Enterotoxins) RN - 0 (Escherichia coli Proteins) RN - 0 (MUC2 protein, human) RN - 0 (Mucin-2) RN - 0 (Mucins) SB - IM MH - *Bacterial Toxins/genetics/metabolism MH - Diarrhea MH - Enterocytes MH - *Enterotoxigenic Escherichia coli/metabolism MH - Enterotoxins/metabolism MH - *Escherichia coli Infections/microbiology MH - *Escherichia coli Proteins/genetics/metabolism MH - Humans MH - Intestine, Small MH - Mucin-2/genetics/metabolism MH - Mucins/metabolism PMC - PMC8853678 OTO - NOTNLM OT - Escherichia OT - diarrhea OT - enterotoxins OT - mucinase OT - proteases COIS- The authors declare no conflict of interest. EDAT- 2021/11/23 06:00 MHDA- 2022/04/21 06:00 PMCR- 2022/08/17 CRDT- 2021/11/22 17:15 PHST- 2021/11/23 06:00 [pubmed] PHST- 2022/04/21 06:00 [medline] PHST- 2021/11/22 17:15 [entrez] PHST- 2022/08/17 00:00 [pmc-release] AID - 00572-21 [pii] AID - iai.00572-21 [pii] AID - 10.1128/IAI.00572-21 [doi] PST - ppublish SO - Infect Immun. 2022 Feb 17;90(2):e0057221. doi: 10.1128/IAI.00572-21. Epub 2021 Nov 22.