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Infection and Immunity, October 2005, p. 6479-6487, Vol. 73, No. 10
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.10.6479-6487.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Apoptotic Response to Pneumolysin Is Toll-Like Receptor 4 Dependent and Protects against Pneumococcal Disease

Amit Srivastava,1 Philipp Henneke,2 Alberto Visintin,3 Sarah C. Morse,1 Victoria Martin,1 Claire Watkins,1 James C. Paton,4 Michael R. Wessels,1 Douglas T. Golenbock,3 and Richard Malley1*

Division of Infectious Diseases, Department of Medicine, Children's Hospital, Boston, Massachusetts,1 Children's Hospital, Freiburg University, Freiburg, Germany,2 Division of Infectious Diseases, Department of Medicine, University of Massachusetts, Worcester, Massachusetts,3 School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide 5005, Australia4

Received 23 February 2005/ Returned for modification 22 April 2005/ Accepted 10 June 2005

Pneumolysin, the cholesterol-dependent cytolysin of Streptococcus pneumoniae, induces inflammatory and apoptotic events in mammalian cells. Toll-like receptor 4 (TLR4) confers resistance to pneumococcal infection via its interaction with pneumolysin, but the underlying mechanisms remain to be identified. In the present study, we found that pneumolysin-induced apoptosis is also mediated by TLR4 and confers protection against invasive disease. The interaction between TLR4 and pneumolysin is direct and specific; ligand-binding studies demonstrated that pneumolysin binds to TLR4 but not to TLR2. Involvement of TLR4 in pneumolysin-induced apoptosis was demonstrated in several complementary experiments. First, macrophages from wild-type mice were significantly more prone to pneumolysin-induced apoptosis than cells from TLR4-defective mice. In gain-of-function experiments, we found that epithelial cells expressing TLR4 and stimulated with pneumolysin were more likely to undergo apoptosis than cells expressing TLR2. A specific TLR4 antagonist, B1287, reduced pneumolysin-mediated apoptosis in wild-type cells. This apoptotic response was also partially caspase dependent as preincubation of cells with the pan-caspase inhibitor zVAD-fmk reduced pneumolysin-induced apoptosis. Finally, in a mouse model of pneumococcal infection, pneumolysin-producing pneumococci elicited significantly more upper respiratory tract cell apoptosis in wild-type mice than in TLR4-defective mice, and blocking apoptosis by administration of zVAD-fmk to wild-type mice resulted in a significant increase in mortality following nasopharyngeal pneumococcal exposure. Overall, our results strongly suggest that protection against pneumococcal disease is dependent on the TLR4-mediated enhancement of pneumolysin-induced apoptosis.

* Corresponding author. Mailing address: Children's Hospital, Division of Infectious Diseases, 300 Longwood Avenue, Boston, MA 02115. Phone: (617) 919-2902. Fax: (617) 730-0255. E-mail: richard.malley{at}childrens.harvard.edu.

Editor: J. N. Weiser

Infection and Immunity, October 2005, p. 6479-6487, Vol. 73, No. 10
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.10.6479-6487.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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