Host- derived CEACAM-laden vesicles engage enterotoxigenic Escherichia coli for elimination and toxin neutralization

• 成果类型: Article
• 署名作者: Sheikh, Alaullah; Ganguli, Debayan; Vickers, Tim J.; Singer, Bernhard B.; Foulke, Jennifer; Akhtar, Marjahan; Khatoon, Nazia; Setu, Bipul; Basu, Supratim; Harro, Clayton; Maier, Nicole; Beatty, Wandy L.; Chakraborty, Subhra; Bhuiyan, Taufiqur R.; Qadri, Firdausi; Donowitz, Mark; Fleckenstein, James M.
• 署名单位: Washington University (WUSTL); University of Duisburg Essen; Johns Hopkins University; International Centre for Diarrhoeal Disease Research (ICDDR); Johns Hopkins University; Johns Hopkins Bloomberg School of Public Health; Washington University (WUSTL); US Department of Veterans Affairs; Veterans Health Administration (VHA)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14150
• DOI: 10.1073/pnas.2410679121
• 发表日期: 2024-09-17
• 关键词: heat-labile enterotoxin; global enteric multicenter; antigen-related antigens; carcinoembryonic antigen; binding-protein; enterocyte microvillus; membrane-vesicles; mucus layers; diarrhea; CHILDREN

摘要

Enterotoxigenic Escherichia coli (ETEC) cause hundreds of millions of diarrheal illnesses annually ranging from mildly symptomatic cases to severe, life- threatening cholera- like diarrhea. Although ETEC are associated with long- term sequelae including malnutrition, the acute diarrheal illness is largely self- limited. Recent studies indicate that in addition to causing diarrhea, the ETEC heat- labile toxin (LT) modulates the expression of many genes in intestinal epithelia, including carcinoembryonic cell adhesion molecules (CEACAMs) which ETEC exploit as receptors, enabling toxin delivery. Here, however, we demonstrate that LT also enhances the expression of CEACAMs on extracellular vesicles (EV) shed by intestinal epithelia and that CEACAM-laden EV increase in abundance during human infections, mitigate pathogen-host interactions, scavenge free ETEC toxins, and accelerate ETEC clearance from the gastrointestinal tract. Collectively, these findings indicate that CEACAMs play a multifaceted role in ETEC pathogen-host interactions, transiently favoring the pathogen, but ultimately contributing to innate responses that extinguish these common infections.