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Infect. Immun. doi:10.1128/IAI.01141-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Flagellin-dependent and -independent inflammatory responses following infection by enteropathogenic Escherichia coli (EPEC) and Citrobacter rodentium

Division of Gastroenterology, BC's Children's Hospital, Vancouver, BC, Canada, Institute of Systems Biology, Seattle, WA, USA, and Division of Infectious Disease and Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada

^* To whom correspondence should be addressed. Email: bvallance{at}cw.bc.ca.

	Abstract

Enteropathogenic Escherichia coli (EPEC) and the murine pathogen Citrobacter rodentium belong to the attaching & effacing (A/E) family of bacterial pathogens. These non-invasive bacteria infect intestinal enterocytes using a type three secretion system (T3SS), leading to diarrheal disease and intestinal inflammation. While flagellin, the secreted product of the EPEC fliC gene, causes the release of interleukin (IL)-8 from epithelial cells, it is unclear whether A/E bacteria also trigger epithelial inflammatory responses that are FliC-independent. The aims of this study were to characterize the FliC-dependence or independence of epithelial inflammatory responses to direct infection by EPEC or C. rodentium. Following infection of Caco-2 intestinal epithelial cells by wild type and fliC EPEC, a rapid activation of several pro-inflammatory genes including IL-8, MCP-1, MIP3 and -defensin-2 occurred in a FliC-dependent manner. These responses were accompanied by MAPK activation as well as the TLR5-dependent activation of NF-kB. At later infection time points, a subset of these pro-inflammatory genes (IL-8, MIP3) was also induced in cells infected with fliC EPEC. The non-motile A/E pathogen C. rodentium also triggered similar innate responses through a TLR5-independent but partially NF-kB-dependent mechanism. Moreover, the EPEC FliC-independent responses were increased in the absence of the LEE (locus of enterocyte effacement) encoded T3SS, suggesting that translocated bacterial effectors suppress rather than cause the FliC-independent inflammatory response. Thus we demonstrate that infection of intestinal epithelial cells by A/E pathogens can trigger an array of pro-inflammatory responses from epithelial cells through both FliC-dependent and -independent pathways, expanding our understanding of the innate epithelial response to infection by these pathogens.