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J. Biol. Chem., Vol. 282, Issue 39, 28700-28708, September 28, 2007

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Role of p38 MAP Kinase and Transforming Growth Factor- Signaling in Transepithelial Migration of Invasive Bacterial Pathogens^*

Christoph Beisswenger, Carolyn B. Coyne, Mikhail Shchepetov, and Jeffrey N. Weiser¹

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

Streptococcus pneumoniae and Haemophilus influenzae are human pathogens that often asymptomatically colonize the mucosal surface of the upper respiratory tract, but also occasionally cause invasive disease. The ability of these species to traverse the epithelium of the airway mucosa was modeled in vitro using polarized respiratory epithelial cells in culture. Migration across the epithelial barrier was preceded by loss of transepithelial resistance. Membrane products of S. pneumoniae that included lipoteichoic acid induced disruption of the epithelial barrier in a Toll-like receptor 2-dependent manner. This result correlates with a recent genetic study that associates increased TLR2 signaling with increased rates of invasive pneumococcal disease in humans. Loss of transepithelial resistance by the TLR2 ligand correlated with activation of p38 MAP kinase and transforming growth factor (TGF)- signaling. Activation of p38 MAPK and TGF- signaling in epithelial cells upon nasal infection with S. pneumoniae was also demonstrated in vivo. Inhibition of either p38 MAPK or TGF- signaling was sufficient to inhibit the migration of S. pneumoniae or H. influenzae. Our data shows that diverse bacteria utilize common mechanisms, including MAPK and TGF- signaling pathways to disrupt epithelial barriers and promote invasion.

Received for publication, April 30, 2007 , and in revised form, July 19, 2007.

^* This work was supported by United States Public Health Service Grants AI 44231 and AI 138446 (to J. N. W.) and immunohistochemical studies were performed at the Morphology Core of the Center for the Molecular Studies of Liver and Digestive Disease supported by Center Grant P30 DK50306. 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: 402A Johnson Pavilion, Dept. of Microbiology and Pediatrics, University of Pennsylvania, Philadelphia, PA 19104-6076. Tel.: 215-573-3511; Fax: 215-573-4856; E-mail: weiser{at}mail.med.upenn.edu.

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