title: The WxxxE effector EspT triggers expression of immune mediators in an Erk/JNK and NF-κB-dependent manner.
abstract: Enteropathogenic Escherichia coli (EPEC), enterohaemorrhagic E. coli (EHEC) and Citrobacter rodentium colonize their respective hosts while forming attaching and effacing lesions. Their infection strategy relies on translocation of a battery of type III secretion system effectors, including Map, EspM and EspT, which belong to the WxxxE/SopE family of guanine nucleotide exchange factors. Using the C. rodentium mouse model we found that EspT triggers expression of KC and TNFα in vivo. Indeed, a growing body of evidence suggests that, in addition to subversion of actin dynamics, the SopE and the WxxxE effectors activate signalling pathways involved in immune responses. In this study we found that EspT induces expression of the pro-inflammatory mediators cyclooxygenase-2 (COX-2) an enzyme involved in production of prostaglandin E(2) (PGE2), interleukin (Il)-8 and Il-1β in U937 human macrophages by activating the nuclear factor kappa-B (NF-κB), the extracellular signal-regulated kinases 1 and 2 (Erk1/2) and c-Jun N-terminal kinase (JNK) pathways. Since EspT modulates the activation of Cdc42 and Rac1, which mediates bacterial invasion into epithelial cells, we investigated the involvement of these Rho GTPases and bacterial invasion on pro-inflammatory responses and found that (i) Rac1, but not Cdc42, is involved in EspT-induced Il-8 and Il-1β secretion and (ii) cytochalasin D inhibits EspT-induced EPEC invasion into U937 but not Il-8 or Il-1β secretion. These results suggest that while EPEC translocates a number of effectors (i.e. NleC, NleD, NleE, NleH) that inhibit inflammation, a subset of strains, which encode EspT, employ an infection strategy that also involves upregulation of immune mediators.
authors.affiliation: Centre for Molecular Microbiology and Infection, Division of Cell and Molecular Biology, Imperial College, London SW7 2AZ, UK.
authors.forename: Benoit
authors.initials: B
authors.lastname: Raymond
authors.forename: Valerie F
authors.initials: VF
authors.lastname: Crepin
authors.forename: James W
authors.initials: JW
authors.lastname: Collins
authors.forename: Gad
authors.initials: G
authors.lastname: Frankel
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000276:immunology; D015638:Cytochalasin D / Q000494:pharmacology; D015232:Dinoprostone / Q000276:immunology; D004195:Disease Models, Animal; D054308:Enteropathogenic Escherichia coli / Q000187:drug effects / Q000276:immunology / Q000472:pathogenicity*; D029968:Escherichia coli Proteins / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007249:Inflammation / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D016209:Interleukin-8 / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000276:immunology*; D021381:Protein Transport; D020298:U937 Cells; D020830:rac1 GTP-Binding Protein / Q000276:immunology
chemical_list: C508606:CXCL8 protein, human; D029968:Escherichia coli Proteins; D053583:Interleukin-1beta; D016209:Interleukin-8; D016328:NF-kappa B; C107953:RAC1 protein, human; C543138:espT protein, E coli; D015638:Cytochalasin D; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein; D015232:Dinoprostone