HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lee, J. Articles by Kornfeld, H. Search for Related Content PubMed PubMed Citation Articles by Lee, J. Articles by Kornfeld, H.

Macrophage Apoptosis in Response to High Intracellular Burden of Mycobacterium tuberculosis Is Mediated by a Novel Caspase-Independent Pathway¹

Jinhee Lee^*, Heinz G. Remold, Michael H. Ieong and Hardy Kornfeld^2,*

^* Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655; Division of Rheumatology and Immunology, Brigham and Women’s Hospital, Boston, MA 02115; and Pulmonary Center, Boston University School of Medicine, Boston, MA 02118

We previously reported that macrophage exposure to attenuated strains of pathogenic mycobacteria at multiplicities of infection (MOI) 10 triggers TNF--mediated apoptosis which reduces the viability of intracellular bacilli. Virulent strains were found to suppress macrophage apoptosis, and it was proposed that apoptosis is an innate defense against intracellular Mycobacterium tuberculosis analogous to apoptosis of virus-infected cells. The potential similarity of host cell responses to intracellular infection with mycobacteria and viruses suggests that M. tuberculosis might lyse infected macrophage when that niche is no longer needed. To investigate this question, we challenged murine macrophages with high intracellular bacillary loads. A sharp increase in cytolysis within 24 h was observed at MOI 25. The primary death mode was apoptosis, based on nuclear morphology and phosphatidyl serine exposure, although the apoptotic cells progressed rapidly to necrosis. Apoptosis at high MOI differs markedly from low MOI apoptosis: it is potently induced by virulent M. tuberculosis, it is TNF--independent, and it does not reduce mycobacterial viability. Caspase inhibitors failed to prevent high MOI apoptosis, and macrophages deficient in caspase-3, MyD88, or TLR4 were equally susceptible as wild type. Apoptosis was reduced in the presence of cathepsin inhibitors, suggesting the involvement of lysosomal proteases in this novel death response. We conclude that the presence of high numbers of intracellular M. tuberculosis bacilli triggers a macrophage cell death pathway that could promote extracellular spread of infection and contribute to the formation of necrotic lesions in tuberculosis.

This article has been cited by other articles:

				D. M. Kelly, A. M. C. ten Bokum, S. M. O'Leary, M. P. O'Sullivan, and J. Keane Bystander Macrophage Apoptosis after Mycobacterium tuberculosis H37Ra Infection Infect. Immun., January 1, 2008; 76(1): 351 - 360. [Abstract] [Full Text] [PDF]

				A. B. Yadav and A. Misra Enhancement of Apoptosis of THP-1 Cells Infected with Mycobacterium tuberculosis by Inhalable Microparticles and Relevance to Bactericidal Activity Antimicrob. Agents Chemother., October 1, 2007; 51(10): 3740 - 3742. [Abstract] [Full Text] [PDF]

				R. Billeskov, C. Vingsbo-Lundberg, P. Andersen, and J. Dietrich Induction of CD8 T Cells against a Novel Epitope in TB10.4: Correlation with Mycobacterial Virulence and the Presence of a Functional Region of Difference-1 J. Immunol., September 15, 2007; 179(6): 3973 - 3981. [Abstract] [Full Text] [PDF]

				M. P. O'Sullivan, S. O'Leary, D. M. Kelly, and J. Keane A Caspase-Independent Pathway Mediates Macrophage Cell Death in Response to Mycobacterium tuberculosis Infection Infect. Immun., April 1, 2007; 75(4): 1984 - 1993. [Abstract] [Full Text] [PDF]

				R. Sharma, P. Muttil, A. B. Yadav, S. K. Rath, V. K. Bajpai, U. Mani, and A. Misra Uptake of inhalable microparticles affects defence responses of macrophages infected with Mycobacterium tuberculosis H37Ra J. Antimicrob. Chemother., March 1, 2007; 59(3): 499 - 506. [Abstract] [Full Text] [PDF]

				X. Vega-Manriquez, Y. Lopez-Vidal, J. Moran, L. G. Adams, and J. A. Gutierrez-Pabello Apoptosis-Inducing Factor Participation in Bovine Macrophage Mycobacterium bovis-Induced Caspase-Independent Cell Death Infect. Immun., March 1, 2007; 75(3): 1223 - 1228. [Abstract] [Full Text] [PDF]

				S. A. Stanley, J. E. Johndrow, P. Manzanillo, and J. S. Cox The Type I IFN Response to Infection with Mycobacterium tuberculosis Requires ESX-1-Mediated Secretion and Contributes to Pathogenesis J. Immunol., March 1, 2007; 178(5): 3143 - 3152. [Abstract] [Full Text] [PDF]