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First published online 26 October 2004
doi: 10.1242/jcs.01500
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Research Article |
1 Epithelial Pathobiology Division, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA
2 Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, GA 30322, USA
3 Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA
4 Department of Anatomy, University of Virginia, Charlottesville, Virginia 22908-0732, USA
* Author for correspondence (e-mail: agewirt{at}emory.edu)
Accepted 18 August 2004
Apical colonization of polarized epithelia by Salmonella typhimurium results in translocation of flagellin to the basolateral membrane domain, thus enabling activation of toll-like receptor 5 (TLR5)-mediated pro-inflammatory gene expression. Such flagellin transcytosis occurred without a change in epithelial permeability to 40 kDa FITC dextran, did not require bacterial motility and was independent of transepithelial movement of intact bacteria. Flagellin transcytosis was blocked at 20°C, suggesting dependence on vesicular transport consistent with results from confocal microscopy that showed flagellin independent of bacteria inside epithelial cells. Furthermore, vesicles isolated from S. typhimurium-infected epithelia were highly enriched in flagellin. Flagellin transcytosis was dependent upon genes of Salmonella pathogenicity island (SPI)-2, which alter vesicular trafficking, but independent of SPI-1 that mediates bacterial invasion. Furthermore, such SPI-2 mutants were unable to mediate the localization of flagellin into intracellular vesicles consistent with flagellin transcytosis mediated by a S. typhimurium take-over of host vesicle trafficking pathways. As a result of their inability to transcytose flagellin, apical colonization by SPI-2 mutants induced substantially less epithelial IL-8 secretion than wild-type strains suggesting that such SPI-2 mediated transcytosis of flagellin plays a role in the pathogenesis of the mucosal inflammation characteristic of human Salmonellosis.
Key words: Toll-like receptor 5 (TLR5), Inflammation, IL-8, Cell polarity
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