CEACAMs serve as toxin-stimulated receptors for enterotoxigenic Escherichia coli

Alaullah Sheikh, Brunda Tumala, Tim J. Vickers, David Alvarado, Matthew A. Ciorba, Taufiqur Rahman Bhuiyan, Firdausi Qadri, Bernhard B. Singer, James M. Fleckenstein

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

The enterotoxigenic Escherichia coli (ETEC) are among the most common causes of diarrheal illness and death due to diarrhea among young children in low-/middle-income countries (LMICs). ETEC have also been associated with important sequelae including malnutrition and stunting, placing children at further risk of death from diarrhea and other infections. Our understanding of the molecular pathogenesis of acute diarrheal disease as well as the sequelae linked to ETEC are still evolving. It has long been known that ETEC heat-labile toxin (LT) activates production of cAMP in the cell, signaling the modulation of cellular ion channels that results in a net efflux of salt and water into the intestinal lumen, culminating in watery diarrhea. However, as LT also promotes ETEC adhesion to intestinal epithelial cells, we postulated that increases in cAMP, a critical cellular “second messenger,” may be linked to changes in cellular architecture that favor pathogen–host interactions. Indeed, here we show that ETEC use LT to up-regulate carcinoembryonic antigenrelated cell adhesion molecules (CEACAMs) on the surface of small intestinal epithelia, where they serve as critical bacterial receptors. Moreover, we show that bacteria are specifically recruited to areas of CEACAM expression, in particular CEACAM6, and that deletion of this CEACAM abrogates both bacterial adhesion and toxin delivery. Collectively, these results provide a paradigm for the molecular pathogenesis of ETEC in which the bacteria use toxin to drive up-regulation of cellular targets that enhances subsequent pathogen–host interactions.

Original languageEnglish
Pages (from-to)29055-29062
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number46
DOIs
StatePublished - Nov 17 2020

Keywords

  • Enterotoxin | CEACAM | diarrhea

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