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The apoptotic response to pneumolysin is Toll-like receptor 4 dependent and protects against pneumococcal disease.

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.

journal_name

Infect Immun

journal_title

Infection and immunity

authors

Srivastava A,Henneke P,Visintin A,Morse SC,Martin V,Watkins C,Paton JC,Wessels MR,Golenbock DT,Malley R

doi

10.1128/IAI.73.10.6479-6487.2005

keywords:

subject

Has Abstract

pub_date

2005-10-01 00:00:00

pages

6479-87

issue

eissn

0019-9567

issn

1098-5522

pii

73/10/6479

journal_volume

pub_type

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The apoptotic response to pneumolysin is Toll-like receptor 4 dependent and protects against pneumococcal disease.