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Role of the Lipopolysaccharide-CD14 Complex for the Activity of Hemolysin from Uropathogenic Escherichia coli

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, S-17177 Stockholm, Sweden,¹ Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin 53706,² Department of Medical Microbiology and Immunology, University of Pécs, 7624 Pécs, Hungary,³ Wallenberg Laboratory, Sahlgrenska University Hospital, S-41345 Göteborg, Sweden⁴

Received 15 June 2006/ Returned for modification 19 September 2006/ Accepted 31 October 2006

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 proinflammatory mediator; however, it is not known whether LPS contributes to cell signaling induced by those microbial components to which it is attached. This is partly due to the common view that LPS present in bacterial component preparations is an experimental artifact. The Escherichia coli exotoxin hemolysin (Hly) is a known inducer of proinflammatory 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 investigated whether it is required as a cofactor for the activity of Hly. We found that the LPS/Hly complex exploits the CD14/LPS-binding protein 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.

Published ahead of print on 13 November 2006.

Editor: F. C. Fang

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