| Incomplete activation of macrophage apoptosis during intracellular replication of Legionella pneumophila. | |
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MedLine Citation:
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PMID: 16113249 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The ability of the intracellular bacterium Legionella pneumophila to cause disease is totally dependent on its ability to modulate the biogenesis of its phagosome and to replicate within alveolar cells. Upon invasion, L. pneumophila activates caspase-3 in macrophages, monocytes, and alveolar epithelial cells in a Dot/Icm-dependent manner that is independent of the extrinsic or intrinsic pathway of apoptosis, suggesting a novel mechanism of caspase-3 activation by this intracellular pathogen. We have shown that the inhibition of caspase-3 prior to infection results in altered biogenesis of the L. pneumophila-containing phagosome and in an inhibition of intracellular replication. In this report, we show that the preactivation of caspase-3 prior to infection does not rescue the intracellular replication of L. pneumophila icmS, icmR, and icmQ mutant strains. Interestingly, preactivation of caspase-3 through the intrinsic and extrinsic pathways of apoptosis in both human and mouse macrophages inhibits intracellular replication of the parental stain of L. pneumophila. Using single-cell analysis, we show that intracellular L. pneumophila induces a robust activation of caspase-3 during exponential replication. Surprisingly, despite this robust activation of caspase-3 in the infected cell, the host cell does not undergo apoptosis until late stages of infection. In sharp contrast, the activation of caspase-3 by apoptosis-inducing agents occurs concomitantly with the apoptotic death of all cells that exhibit caspase-3 activation. It is only at a later stage of infection, and concomitant with the termination of intracellular replication, that the L. pneumophila-infected cells undergo apoptotic death. We conclude that although a robust activation of caspase-3 is exhibited throughout the exponential intracellular replication of L. pneumophila, apoptotic cell death is not executed until late stages of the infection, concomitant with the termination of intracellular replication. |
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Authors:
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Alaeddin Abu-Zant; Marina Santic; Maelle Molmeret; Snake Jones; Jürgen Helbig; Yousef Abu Kwaik |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Infection and immunity Volume: 73 ISSN: 0019-9567 ISO Abbreviation: Infect. Immun. Publication Date: 2005 Sep |
Date Detail:
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Created Date: 2005-08-22 Completed Date: 2005-10-12 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 0246127 Medline TA: Infect Immun Country: United States |
Other Details:
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Languages: eng Pagination: 5339-49 Citation Subset: IM |
Affiliation:
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Department of Microbiology, University of Louisville College of Medicine, Louisville, KY 40292, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / physiology* Bacterial Proteins / genetics Caspase 3 Caspases / metabolism Cell Proliferation / drug effects Enzyme Activation / immunology Enzyme Inhibitors / pharmacology Humans Intracellular Fluid / enzymology, immunology, microbiology Legionella pneumophila / drug effects, genetics, growth & development* Macrophage Activation / immunology* Macrophages / immunology*, microbiology* Mice Molecular Chaperones / genetics Mutation Staurosporine / pharmacology Tumor Necrosis Factor-alpha / physiology U937 Cells |
| Grant Support | |
ID/Acronym/Agency:
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R01AI43965/AI/NIAID NIH HHS; R21AI038410-06A1/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Bacterial Proteins; 0/Enzyme Inhibitors; 0/ICMQ protein, Legionella pneumophila; 0/IcmR protein, Legionella pneumophila; 0/IcmS protein, Legionella pneumophila; 0/Molecular Chaperones; 0/Tumor Necrosis Factor-alpha; 62996-74-1/Staurosporine; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases |
| Comments/Corrections | |
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