title: Heat-labile enterotoxin-induced activation of NF-κB and MAPK pathways in intestinal epithelial cells impacts enterotoxigenic Escherichia coli (ETEC) adherence.
abstract: Enterotoxigenic Escherichia coli (ETEC) causes human morbidity and mortality in developing nations and is an emerging threat to food safety in developed nations. The ETEC heat-labile enterotoxin (LT) not only causes diarrheal disease by deregulating host adenylate cyclase, but also enhances ETEC adherence to intestinal epithelial cells. The mechanism governing this LT pro-adherence phenotype is unclear. Here we investigated intestinal epithelial cell signal transduction pathways activated by ETEC and quantified the relative importance of these host pathways to LT-induced ETEC adherence. We show that ETEC activates both NF-κB and mitogen-activated protein kinase signalling pathways through mechanisms that are primarily dependent upon LT. LT-induced NF-κB activation depends upon the cAMP-dependent activation of the Ras-like GTPase Rap1 but is independent of protein kinase A (PKA). By using inhibitors of these pathways, we demonstrate that inhibiting the p38 mitogen-activated protein kinase prevents LT from increasing ETEC adherence. By contrast, the LT pro-adherence phenotype appears unrelated to both LT-induced Rap1 activity and to subsequent NF-κB activation. We speculate that LT may alter host signal transduction to induce the presentation of ligands for ETEC adhesins in such a way that promotes ETEC adherence. Our findings provide insight into previously unexplored functions of LT and their relative importance to ETEC virulence.
authors.affiliation: Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Wang
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Gao
authors.forename: Philip R
authors.initials: PR
authors.lastname: Hardwidge
mesh_terms: D001422:Bacterial Adhesion; D001427:Bacterial Toxins / Q000378:metabolism*; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054307:Enterotoxigenic Escherichia coli / Q000378:metabolism / Q000502:physiology*; D004768:Enterotoxins / Q000378:metabolism*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000382:microbiology*; D029968:Escherichia coli Proteins / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D007413:Intestinal Mucosa / Q000166:cytology; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D016328:NF-kappa B; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; C027538:heat-labile enterotoxin, E coli; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases