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https://hdl.handle.net/2440/27610
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dc.contributor.author | Srivastava, A. | - |
dc.contributor.author | Henneke, P. | - |
dc.contributor.author | Visintin, A. | - |
dc.contributor.author | Morse, S. | - |
dc.contributor.author | Martin, V. | - |
dc.contributor.author | Watkins, C. | - |
dc.contributor.author | Paton, J. | - |
dc.contributor.author | Wessels, M. | - |
dc.contributor.author | Golenbock, D. | - |
dc.contributor.author | Malley, R. | - |
dc.date.issued | 2005 | - |
dc.identifier.citation | Infection and Immunity, 2005; 73(10):6479-6487 | - |
dc.identifier.issn | 0019-9567 | - |
dc.identifier.issn | 1098-5522 | - |
dc.identifier.uri | http://hdl.handle.net/2440/27610 | - |
dc.description | Copyright © 2005, American Society for Microbiology | - |
dc.description.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. | - |
dc.language.iso | en | - |
dc.publisher | Amer Soc Microbiology | - |
dc.source.uri | http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1230904&rendertype=abstract | - |
dc.subject | Nasopharynx | - |
dc.subject | Macrophages | - |
dc.subject | Animals | - |
dc.subject | Mice, Inbred Strains | - |
dc.subject | Mice | - |
dc.subject | Streptococcus pneumoniae | - |
dc.subject | Pneumococcal Infections | - |
dc.subject | Caspases | - |
dc.subject | Lipopolysaccharides | - |
dc.subject | Amino Acid Chloromethyl Ketones | - |
dc.subject | Bacterial Proteins | - |
dc.subject | Streptolysins | - |
dc.subject | Apoptosis | - |
dc.subject | Caspase Inhibitors | - |
dc.title | The apoptotic response to pneumolysin is toll-like receptor 4 dependent and protects against pneumococcal disease | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1128/IAI.73.10.6479-6487.2005 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Paton, J. [0000-0001-9807-5278] | - |
Appears in Collections: | Aurora harvest 2 Molecular and Biomedical Science publications |
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