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      1. Author :
        Srivastava, Amit; Henneke, Philipp; Visintin, Alberto; Morse, Sarah C; Martin, Victoria; Watkins, Claire; Paton, James C; Wessels, Michael R; Golenbock, Douglas T; Malley, Richard
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2005
      5. Publication :
        Infection and immunity
      6. Products :
      7. Volume :
        73
      8. Issue :
        10
      9. Page Numbers :
        6479-6487
      10. Research Area :
        N/A
      11. Keywords :
        Amino Acid Chloromethyl Ketones; Animals; Apoptosis; Bacterial Proteins; Caspases; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred Strains; Nasopharynx; Pneumococcal Infections; Streptococcus pneumoniae; Streptolysins; Xen10
      12. 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.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/16177320
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        10001
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