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Infect. Immun. doi:10.1128/IAI.00957-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

ROLE OF THE LPS/CD14 COMPLEX FOR THE ACTIVITY OF HEMOLYSIN FROM UROPATHOGENIC E. COLI

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, S-17177 Stockholm, Sweden; Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706 USA; Department of Medical Microbiology and Immunology, University of Pécs, 7624 Pécs, Hungary; Center for Genome Sciences, Washington University, St Louis, MO 63108 USA

^* To whom correspondence should be addressed. Email: agneta.richter.dahlfors{at}ki.se.

	Abstract

Bacterial pathogens produce a variety of exotoxins, which often become associated with the bacterial outer membrane component lipopolysaccharide (LPS) during their secretion. LPS is a potent pro-inflammatory mediator, however it is not known if LPS contributes to cell signaling induced by those microbial components it is attached to. This is partly due to the common view that LPS present in bacterial component preparations is an experimental artifact. The E. coli exotoxin hemolysin (Hly) is a known inducer of pro-inflammatory signaling in epithelial cells, and the signal-transduction pathway involves fluctuation of the intracellular Ca²⁺-concentration. Since LPS is known to interact with Hly, we investigate whether it is required as a co-factor for Hly's activity. We found that the LPS/Hly complex exploit the CD14/LBP recognition system to bring Hly to the cell membrane where intracellular Ca²⁺ signaling is initiated via specific activation of the small GTPase RhoA. Hly-induced Ca²⁺ signaling was found to occur independently of the LPS-receptor TLR4, suggesting that the role of LPS/CD14 is to deliver Hly to the cell membrane. In contrast, the cytolytic effect triggered by exposure of cells to high Hly concentrations occurs independently of LPS/CD14. Collectively, our data reveal a novel molecular mechanism for toxin delivery in bacterial pathogenesis, where LPS-associated microbial compounds are targeted to the host cell membrane as a consequence of their association with LPS.

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