title: Enteropathogenic E. coli non-LEE encoded effectors NleH1 and NleH2 attenuate NF-κB activation.
abstract: Enteric bacterial pathogens have evolved sophisticated strategies to evade host immune defences. Some pathogens deliver anti-inflammatory effector molecules into the host cell cytoplasm via a type III secretion system (T3SS). Enteropathogenic Escherichia coli (EPEC) inhibits inflammation by an undefined, T3SS-dependent mechanism. Two proteins encoded outside of the EPEC locus of enterocyte effacement (LEE) pathogenicity island, non-LEE-encoded effector H1 (NleH1) and H2 (NleH2), display sequence similarity to Shigella flexneri OspG, which inhibits activation of the pro-inflammatory transcription factor NF-κB. We hypothesized that the anti-inflammatory effects of EPEC were mediated by NleH1 and NleH2. In this study, we examined the effect of NleH1/H2 on the NF-κB pathway. We show that NleH1/H2 are secreted via the T3SS and that transfection of cells with plasmids harbouring nleH1 or nleH2 decreased IKK-β-induced NF-κB activity and attenuated TNF-α-induced degradation of phospho-IκBα by preventing ubiquitination. Serum KC levels were higher in mice infected with ΔnleH1H2 than those infected with WT EPEC, indicating that NleH1/H2 dampen pro-inflammatory cytokine expression. ΔnleH1H2 was cleared more rapidly than WT EPEC while complementation of ΔnleH1H2 with either NleH1 or NleH2 prolonged colonization. Together, these data show that NleH1 and NleH2 function to dampen host inflammation and facilitate EPEC colonization during pathogenesis.
authors.affiliation: Department of Medicine, Section of Digestive Diseases and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Sandhya V
authors.initials: SV
authors.lastname: Royan
authors.forename: Rheinallt M
authors.initials: RM
authors.lastname: Jones
authors.forename: Athanasia
authors.initials: A
authors.lastname: Koutsouris
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Roxas
authors.forename: Kanakeshwari
authors.initials: K
authors.lastname: Falzari
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Weflen
authors.forename: Amy
authors.initials: A
authors.lastname: Kim
authors.forename: Amy
authors.initials: A
authors.lastname: Bellmeyer
authors.forename: Jerrold R
authors.initials: JR
authors.lastname: Turner
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Neish
authors.forename: Ki-Jong
authors.initials: KJ
authors.lastname: Rhee
authors.forename: V K
authors.initials: VK
authors.lastname: Viswanathan
authors.forename: Gail A
authors.initials: GA
authors.lastname: Hecht
mesh_terms: D000818:Animals; D002460:Cell Line; D054308:Enteropathogenic Escherichia coli / Q000235:genetics / Q000276:immunology*; D004927:Escherichia coli Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D029968:Escherichia coli Proteins / Q000235:genetics / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*
chemical_list: D029968:Escherichia coli Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha