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Infection and Immunity, April 2007, p. 1984-1993, Vol. 75, No. 4
0019-9567/07/$08.00+0     doi:10.1128/IAI.01107-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Caspase-Independent Pathway Mediates Macrophage Cell Death in Response to Mycobacterium tuberculosis Infection{triangledown}

Mary P. O'Sullivan, Seonadh O'Leary, Deirdre M. Kelly, and Joseph Keane*

Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, and St. James's Hospital, Dublin, Ireland

Received 14 July 2006/ Returned for modification 6 September 2006/ Accepted 4 January 2007

Macrophages can undergo apoptosis after infection with Mycobacterium tuberculosis. This macrophage response deprives the bacillus of its niche cell and supports the host response through better antigen presentation. The intracellular pathways of apoptosis that elaborate this macrophage response are not well understood. To address this issue, we investigated the contribution of various apoptosis pathways to M. tuberculosis-induced macrophage cell death. We found that macrophages die in a caspase-independent manner after infection with M. tuberculosis (at multiplicities of infection ranging from 1 to 20). There was evidence for the involvement of both the mitochondria (cleavage of Bid) and the lysosomes (cathepsin-mediated DNA fragmentation) in this cell death pathway. Dying macrophages displayed several features typical of apoptosis, including DNA fragmentation, nuclear condensation, and exposure of phosphatidylserine on the plasma membrane. However, nuclear fragmentation was not observed, which suggests that M. tuberculosis-induced cell death differs in some respects from classical apoptosis. This novel mechanism of cell death was blocked by serine protease inhibitors. A better understanding of this protective macrophage response may direct new vaccine and treatment options.

* Corresponding author. Mailing address: St. James's Hospital, CResT, Dublin 8, Ireland. Phone: 353 1 410 3920. Fax: 353 1 410 3549. E-mail: jkeane{at}stjames.ie.

{triangledown} Published ahead of print on 5 February 2007.

Editor: J. L. Flynn

Infection and Immunity, April 2007, p. 1984-1993, Vol. 75, No. 4
0019-9567/07/$08.00+0     doi:10.1128/IAI.01107-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Li, J. H., D'Alessio, A., Pober, J. S. (2009). Lipopolysaccharide Can Trigger a Cathepsin B-Dependent Programmed Death Response in Human Endothelial Cells. Am. J. Pathol. 175: 1124-1135 [Abstract] [Full Text]  
  • Kelly, D. M., ten Bokum, A. M. C., O'Leary, S. M., O'Sullivan, M. P., Keane, J. (2008). Bystander Macrophage Apoptosis after Mycobacterium tuberculosis H37Ra Infection. Infect. Immun. 76: 351-360 [Abstract] [Full Text]  


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