Enteropathogenic Escherichia coli (EPEC) inactivate innate immune responses prior to compromising epithelial barrier function.
Enteropathogenic Escherichia coli (EPEC) infection of the human small intestine induces severe watery diarrhoea linked to a rather weak inflammatory response despite EPEC's in vivo capacity to disrupt epithelial barrier function. Here, we demonstrate that EPEC flagellin triggers the secretion of the pro-inflammatory cytokine, interleukin (IL)-8, from small (Caco-2) and large (T84) intestinal epithelia model systems. Interestingly, IL-8 secretion required basolateral infection of T84 cells implying that flagellin must penetrate the epithelial barrier. In contrast, apical infection of Caco-2 cells induced IL-8 secretion but less potently than basolateral infections. Importantly, infection of Caco-2, but not T84 cells rapidly inhibited IL-8 secretion by a mechanism dependent on the delivery of effectors through a translocation system encoded on the locus of enterocyte effacement (LEE). Moreover, EPEC prevents the phosphorylation-associated activation of multiple kinase pathways regulating IL-8 gene transcription by a mechanism apparently independent of LEE-encoded effectors and four non-LEE-encoded effectors. Crucially, our studies reveal that EPEC inhibits the capacity of the cells to secrete IL-8 in response to bacterial antigens and inflammatory cytokines prior to disrupting barrier function by a distinct mechanism. Thus, these findings also lend themselves to a plausible mechanism to explain the absence of a strong inflammatory response in EPEC-infected humans.
Ruchaud-Sparagano
Marie-Hélène
MH
Institute for Cell and Molecular Biosciences, Medical School, University of Newcastle, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
Maresca
Marc
M
Kenny
Brendan
B
D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D016764:Cell Polarity; D054308:Enteropathogenic Escherichia coli / Q000502:physiology*; D004847:Epithelial Cells / Q000276:immunology / Q000382:microbiology*; D029968:Escherichia coli Proteins / Q000378:metabolism*; D005408:Flagellin / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007113:Immunity, Innate; D016209:Interleukin-8 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology*; D007421:Intestine, Small / Q000276:immunology / Q000382:microbiology; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation
D029968:Escherichia coli Proteins; D020672:I-kappa B Proteins; D016209:Interleukin-8; D016328:NF-kappa B; D005408:Flagellin