title: Attaching and effacing bacterial effector NleC suppresses epithelial inflammatory responses by inhibiting NF-κB and p38 mitogen-activated protein kinase activation.
abstract: Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli are noninvasive attaching and effacing (A/E) bacterial pathogens that cause intestinal inflammation and severe diarrheal disease. These pathogens utilize a type III secretion system to deliver effector proteins into host epithelial cells, modulating diverse cellular functions, including the release of the chemokine interleukin-8 (IL-8). While studies have implicated the effectors NleE (non-locus of enterocyte effacement [LEE]-encoded effector E) and NleH1 in suppressing IL-8 release, by preventing NF-κB nuclear translocation, the impact of these effectors only partially replicates the immunosuppressive actions of wild-type EPEC, suggesting another effector or effectors are involved. Testing an array of EPEC mutants, we identified the non-LEE-encoded effector C (NleC) as also suppressing IL-8 release. Infection by ΔnleC EPEC led to exaggerated IL-8 release from infected Caco-2 and HT-29 epithelial cells. NleC localized to EPEC-induced pedestals, with signaling studies revealing NleC inhibits both NF-κB and p38 mitogen-activated protein kinase (MAPK) activation. Using Citrobacter rodentium, a mouse-adapted A/E bacterium, we found that ΔnleC and wild-type C. rodentium-infected mice carried similar pathogen burdens, yet ΔnleC strain infection led to worsened colitis. Similarly, infection with ΔnleC C. rodentium in a cecal loop model induced significantly greater chemokine responses than infection with wild-type bacteria. These studies thus advance our understanding of how A/E pathogens subvert host inflammatory responses.
authors: Division of Gastroenterology, BC's Children's Hospital, Vancouver, British Columbia, Canada V6H 3V4.
authors: Ho Pan
authors: HP
authors: Sham
authors: Stephanie R
authors: SR
authors: Shames
authors: Matthew A
authors: MA
authors: Croxen
authors: Caixia
authors: C
authors: Ma
authors: Justin M
authors: JM
authors: Chan
authors: Mohammed A
authors: MA
authors: Khan
authors: Mark E
authors: ME
authors: Wickham
authors: Wanyin
authors: W
authors: Deng
authors: B Brett
authors: BB
authors: Finlay
authors: Bruce A
authors: BA
authors: Vallance
mesh_terms: D000818:Animals; D001422:Bacterial Adhesion; D018938:Caco-2 Cells; D018925:Chemokines / Q000378:metabolism; D044082:Citrobacter rodentium / Q000235:genetics / Q000472:pathogenicity*; D003092:Colitis / Q000382:microbiology; D004756:Enterobacteriaceae Infections / Q000276:immunology / Q000382:microbiology*; D054308:Enteropathogenic Escherichia coli / Q000235:genetics / Q000472:pathogenicity*; D004847:Epithelial Cells / Q000276:immunology; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D019073:HT29 Cells; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D018925:Chemokines; D029968:Escherichia coli Proteins; D016209:Interleukin-8; D016328:NF-kappa B; C506688:Z0986 protein, E coli; D048051:p38 Mitogen-Activated Protein Kinases