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https://hdl.handle.net/2440/27610
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Type: | Journal article |
Title: | The apoptotic response to pneumolysin is toll-like receptor 4 dependent and protects against pneumococcal disease |
Author: | Srivastava, A. Henneke, P. Visintin, A. Morse, S. Martin, V. Watkins, C. Paton, J. Wessels, M. Golenbock, D. Malley, R. |
Citation: | Infection and Immunity, 2005; 73(10):6479-6487 |
Publisher: | Amer Soc Microbiology |
Issue Date: | 2005 |
ISSN: | 0019-9567 1098-5522 |
Abstract: | 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. |
Keywords: | Nasopharynx Macrophages Animals Mice, Inbred Strains Mice Streptococcus pneumoniae Pneumococcal Infections Caspases Lipopolysaccharides Amino Acid Chloromethyl Ketones Bacterial Proteins Streptolysins Apoptosis Caspase Inhibitors |
Description: | Copyright © 2005, American Society for Microbiology |
DOI: | 10.1128/IAI.73.10.6479-6487.2005 |
Published version: | http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1230904&rendertype=abstract |
Appears in Collections: | Aurora harvest 2 Molecular and Biomedical Science publications |
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