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J. Biol. Chem., Vol. 281, Issue 18, 12994-12998, May 5, 2006

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Epithelial Cells Are Sensitive Detectors of Bacterial Pore-forming Toxins^*

Adam J. Ratner¹, Karen R. Hippe, Jorge L. Aguilar, Matthew H. Bender, Aaron L. Nelson, and Jeffrey N. Weiser

From the Departments of Microbiology and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Epithelial cells act as an interface between human mucosal surfaces and the surrounding environment. As a result, they are responsible for the initiation of local immune responses, which may be crucial for prevention of invasive infection. Here we show that epithelial cells detect the presence of bacterial pore-forming toxins (including pneumolysin from Streptococcus pneumoniae, -hemolysin from Staphylococcus aureus, streptolysin O from Streptococcus pyogenes, and anthrolysin O from Bacillus anthracis) at nanomolar concentrations, far below those required to cause cytolysis. Phosphorylation of p38 MAPK appears to be a conserved response of epithelial cells to subcytolytic concentrations of bacterial poreforming toxins, and this activity is inhibited by the addition of high molecular weight osmolytes to the extracellular medium. By sensing osmotic stress caused by the insertion of a sublethal number of pores into their membranes, epithelial cells may act as an early warning system to commence an immune response, while the local density of toxin-producing bacteria remains low. Osmosensing may thus represent a novel innate immune response to a common bacterial virulence strategy.

Received for publication, October 20, 2005 , and in revised form, March 1, 2006.

^* This work was supported by National Institutes of Health Grants AI054647, AI044231, and AI038446 (to J. N. W.) and AI065450 (to A. J. R.) and by the PIDS-St. Jude Fellowship Program (to A. J. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Microbiology, University of Pennsylvania, Johnson Pavilion 401A, Philadelphia, PA 19104-6076. Tel.: 215-573-3510; Fax: 215-573-4856; E-mail: ratner{at}mail.med.upenn.edu.

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