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Published ahead of print on May 14, 2003, doi:10.1165/rcmb.2002-0310OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 29, pp. 545-551, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.2002-0310OC

Apoptosis Genes in Human Alveolar Macrophages Infected with Virulent or Attenuated Mycobacterium tuberculosis

A Pivotal Role for Tumor Necrosis Factor

Avrum Spira, J. David Carroll*, Gang Liu, Zeeshan Aziz, Vishal Shah, Hardy Kornfeld and Joseph Keane{dagger}

Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts; and Dublin Molecular Medicine Centre, Trinity College, St. James's Hospital, Dublin, Ireland

Address correspondence to: Dr. J. Keane, St. James's Hospital, James's St., Dublin 3, Ireland. E-mail: jkeane{at}stjames.ie

Tumor necrosis factor (TNF)-{alpha}–dependent apoptosis of alveolar macrophages (AM) after infection with avirulent Mycobacterium tuberculosis (Mtb) results in bacillary death and the destruction of a growth niche for the pathogen. This response is minimized after infection with virulent strains of Mtb. To study the genetic control of Mtb-induced apoptosis, we used microarrays to interrogate the expression profile of infected human AM. Although we found variation in gene expression between different donors of AM, a set of genes were constant for each condition. A group of proapoptotic genes were downregulated after infection by virulent Mtb strain H37Rv, whereas infection with avirulent Mtb H37Ra led to a gene expression profile that would favor macrophage apoptosis. Neutralizing TNF in macrophage cultures infected with H37Ra changed the gene expression profile to one that resembled the profile of macrophages infected with H37Rv. These data reveal that apoptosis-related genes are regulated differently by virulent or attenuated Mtb strains, and are consistent with the hypothesis that virulent Mtb interfere with TNF death signaling. Given the importance of TNF in host defense against tuberculosis, the ability to repress the expression of genes activated by TNF may constitute a bacillary virulence mechanism.

Abbreviations: alveolar macrophages, AM • anti-tumor necrosis factor-{alpha} antibody, anti-TNF Ab • M. tuberculosis H37Ra, H37Ra • M. tuberculosis H37Rv, H37Rv • multiplicity of infection, MOI • Mycobacterium tuberculosis, Mtb • tumor necrosis factor-{alpha}, TNF-{alpha}




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