This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gao, L.-Y.
Right arrow Articles by Abu Kwaik, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gao, L.-Y.
Right arrow Articles by Abu Kwaik, Y.

 Previous Article  |  Next Article 

Infection and Immunity, September 1999, p. 4886-4894, Vol. 67, No. 9
0019-9567/99/$04.00+0

Activation of Caspase 3 during Legionella pneumophila-Induced Apoptosis

Lian-Yong Gao and Yousef Abu Kwaik*

Department of Microbiology and Immunology, University of Kentucky Chandler Medical Center, Lexington, Kentucky 40536-0084

Received 3 May 1999/Returned for modification 10 June 1999/Accepted 21 June 1999

The hallmark of Legionnaires' disease is replication of Legionella pneumophila within cells in the alveolar spaces. The mechanisms by which L. pneumophila replicates intracellularly and kills the host cell are largely not understood. We have recently shown that within 3 h of initiation of the infection and prior to intracellular replication, L. pneumophila induces apoptosis in macrophages, alveolar epithelial cells, and peripheral blood monocytes, which correlates with cytopathogenicity (L.-Y. Gao and Y. Abu Kwaik, Infect. Immun. 67:862-870, 1999). In this report, we show that the ability of L. pneumophila to induce apoptosis is, largely, not growth phase regulated. We demonstrate that the induction of apoptosis by L. pneumophila in macrophages is mediated through the activation of caspase 3. The enzymatic activity of caspase 3 to cleave a specific synthetic substrate in vitro is detected in L. pneumophila-infected macrophages at 2 h after infection and is maximal at 3 h, with over 900% increase in activity. The activity of caspase 3 to cleave a specific substrate [poly(ADP-ribose) polymerase, or PARP] in vivo is also detected at 2 h and is maximal at 3 h postinfection. The activity of caspase 3 to cleave the synthetic substrate in vitro and PARP in vivo is blocked by a specific inhibitor of caspase 3. The kinetics of caspase 3 activation correlates with that of L. pneumophila-induced nuclear apoptosis. Inhibition of caspase 3 activity blocks L. pneumophila-induced nuclear apoptosis and cytopathogenicity during early stages of the infection. Consistent with the ability to induce apoptosis, extracellular L. pneumophila also activates caspase 3. Three dotA/icmWXYZ mutants of L. pneumophila that are defective in inducing apoptosis do not induce caspase 3 activation, suggesting that expression and/or export of the apoptosis-inducing factor(s) is regulated by the dot/icm virulence system. This is the first description of the role of caspase 3 activation in induction of nuclear apoptosis in the host cell infected by a bacterial pathogen.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of Kentucky Chandler Medical Center, Lexington, KY 40536-0084. Phone: (606) 323-3873. Fax: (606) 257-8994. E-mail: yabukw{at}pop.uky.edu.

Infection and Immunity, September 1999, p. 4886-4894, Vol. 67, No. 9
0019-9567/99/$04.00+0


This article has been cited by other articles:

  • Ge, J., Xu, H., Li, T., Zhou, Y., Zhang, Z., Li, S., Liu, L., Shao, F. (2009). A Legionella type IV effector activates the NF-{kappa}B pathway by phosphorylating the I{kappa}B family of inhibitors. Proc. Natl. Acad. Sci. USA 106: 13725-13730 [Abstract] [Full Text]  
  • Galka, F., Wai, S. N., Kusch, H., Engelmann, S., Hecker, M., Schmeck, B., Hippenstiel, S., Uhlin, B. E., Steinert, M. (2008). Proteomic Characterization of the Whole Secretome of Legionella pneumophila and Functional Analysis of Outer Membrane Vesicles. Infect. Immun. 76: 1825-1836 [Abstract] [Full Text]  
  • Santic, M., Asare, R., Doric, M., Abu Kwaik, Y. (2007). Host-Dependent Trigger of Caspases and Apoptosis by Legionella pneumophila. Infect. Immun. 75: 2903-2913 [Abstract] [Full Text]  
  • Asare, R., Santic, M., Gobin, I., Doric, M., Suttles, J., Graham, J. E., Price, C. D., Abu Kwaik, Y. (2007). Genetic Susceptibility and Caspase Activation in Mouse and Human Macrophages Are Distinct for Legionella longbeachae and L. pneumophila. Infect. Immun. 75: 1933-1945 [Abstract] [Full Text]  
  • Klumpp, D. J., Rycyk, M. T., Chen, M. C., Thumbikat, P., Sengupta, S., Schaeffer, A. J. (2006). Uropathogenic Escherichia coli Induces Extrinsic and Intrinsic Cascades To Initiate Urothelial Apoptosis. Infect. Immun. 74: 5106-5113 [Abstract] [Full Text]  
  • Molofsky, A. B., Byrne, B. G., Whitfield, N. N., Madigan, C. A., Fuse, E. T., Tateda, K., Swanson, M. S. (2006). Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection. JEM 203: 1093-1104 [Abstract] [Full Text]  
  • Abu-Zant, A., Santic, M., Molmeret, M., Jones, S., Helbig, J., Abu Kwaik, Y. (2005). Incomplete Activation of Macrophage Apoptosis during Intracellular Replication of Legionella pneumophila. Infect. Immun. 73: 5339-5349 [Abstract] [Full Text]  
  • Fortier, A., Min-Oo, G., Forbes, J., Lam-Yuk-Tseung, S., Gros, P. (2005). Single gene effects in mouse models of host: pathogen interactions. J. Leukoc. Biol. 77: 868-877 [Abstract] [Full Text]  
  • Santic, M., Molmeret, M., Abu Kwaik, Y. (2005). Maturation of the Legionella pneumophila-Containing Phagosome into a Phagolysosome within Gamma Interferon-Activated Macrophages. Infect. Immun. 73: 3166-3171 [Abstract] [Full Text]  
  • Derre, I., Isberg, R. R. (2004). Macrophages from Mice with the Restrictive Lgn1 Allele Exhibit Multifactorial Resistance to Legionella pneumophila. Infect. Immun. 72: 6221-6229 [Abstract] [Full Text]  
  • Fischer, S. F., Vier, J., Kirschnek, S., Klos, A., Hess, S., Ying, S., Hacker, G. (2004). Chlamydia Inhibit Host Cell Apoptosis by Degradation of Proapoptotic BH3-only Proteins. JEM 200: 905-916 [Abstract] [Full Text]  
  • Lai, X.-H., Sjostedt, A. (2003). Delineation of the Molecular Mechanisms of Francisella tularensis-Induced Apoptosis in Murine Macrophages. Infect. Immun. 71: 4642-4646 [Abstract] [Full Text]  
  • Tateda, K., Deng, J. C., Moore, T. A., Newstead, M. W., Paine, R. III, Kobayashi, N., Yamaguchi, K., Standiford, T. J. (2003). Hyperoxia Mediates Acute Lung Injury and Increased Lethality in Murine Legionella Pneumonia: The Role of Apoptosis. J. Immunol. 170: 4209-4216 [Abstract] [Full Text]  
  • Eskra, L., Mathison, A., Splitter, G. (2003). Microarray Analysis of mRNA Levels from RAW264.7 Macrophages Infected with Brucella abortus. Infect. Immun. 71: 1125-1133 [Abstract] [Full Text]  
  • Alli, O. A. T., Zink, S., von Lackum, N. K., Abu-Kwaik, Y. (2003). Comparative assessment of virulence traits in Legionella spp.. Microbiology 149: 631-641 [Abstract] [Full Text]  
  • Dellacasagrande, J., Ghigo, E., Raoult, D., Capo, C., Mege, J.-L. (2002). IFN-{gamma}-Induced Apoptosis and Microbicidal Activity in Monocytes Harboring the Intracellular Bacterium Coxiella burnetii Require Membrane TNF and Homotypic Cell Adherence. J. Immunol. 169: 6309-6315 [Abstract] [Full Text]  
  • Neumeister, B., Faigle, M., Lauber, K., Northoff, H., Wesselborg, S. (2002). Legionella pneumophila induces apoptosis via the mitochondrial death pathway. Microbiology 148: 3639-3650 [Abstract] [Full Text]  
  • Zink, S. D., Pedersen, L., Cianciotto, N. P., Abu Kwaik, Y. (2002). The Dot/Icm Type IV Secretion System of Legionella pneumophila Is Essential for the Induction of Apoptosis in Human Macrophages. Infect. Immun. 70: 1657-1663 [Abstract] [Full Text]  
  • Chen, Y.-Q., Zhou, Y.-Q., Wang, M.-H. (2002). Activation of the RON receptor tyrosine kinase protects murine macrophages from apoptotic death induced by bacterial lipopolysaccharide. J. Leukoc. Biol. 71: 359-366 [Abstract] [Full Text]  
  • ARAKAKI, N., HIGA, F., KOIDE, M., TATEYAMA, M., SAITO, A. (2002). Induction of apoptosis of human macrophages in vitro by Legionella longbeachae through activation of the caspase pathway. J Med Microbiol 51: 159-168 [Abstract] [Full Text]  
  • Lai, X.-H., Golovliov, I., Sjostedt, A. (2001). Francisella tularensis Induces Cytopathogenicity and Apoptosis in Murine Macrophages via a Mechanism That Requires Intracellular Bacterial Multiplication. Infect. Immun. 69: 4691-4694 [Abstract] [Full Text]  
  • Pedersen, L. L., Radulic, M., Doric, M., Abu Kwaik, Y. (2001). HtrA Homologue of Legionella pneumophila: an Indispensable Element for Intracellular Infection of Mammalian but Not Protozoan Cells. Infect. Immun. 69: 2569-2579 [Abstract] [Full Text]  
  • Harb, O. S., Abu Kwaik, Y. (2000). Essential Role for the Legionella pneumophila Rep Helicase Homologue in Intracellular Infection of Mammalian Cells. Infect. Immun. 68: 6970-6978 [Abstract] [Full Text]  
  • Alli, O. A. T., Gao, L.-Y., Pedersen, L. L., Zink, S., Radulic, M., Doric, M., Abu Kwaik, Y. (2000). Temporal Pore Formation-Mediated Egress from Macrophages and Alveolar Epithelial Cells by Legionella pneumophila. Infect. Immun. 68: 6431-6440 [Abstract] [Full Text]  
  • Wesson, C. A., Deringer, J., Liou, L. E., Bayles, K. W., Bohach, G. A., Trumble, W. R. (2000). Apoptosis Induced by Staphylococcus aureus in Epithelial Cells Utilizes a Mechanism Involving Caspases 8 and 3. Infect. Immun. 68: 2998-3001 [Abstract] [Full Text]  
  • Diez, E., Yaraghi, Z., MacKenzie, A., Gros, P. (2000). The Neuronal Apoptosis Inhibitory Protein (Naip) Is Expressed in Macrophages and Is Modulated After Phagocytosis and During Intracellular Infection with Legionella pneumophila. J. Immunol. 164: 1470-1477 [Abstract] [Full Text]  
  • Harb, O. S., Abu Kwaik, Y. (2000). Characterization of a Macrophage-Specific Infectivity Locus (milA) of Legionella pneumophila. Infect. Immun. 68: 368-376 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»