Published ahead of print on May 14, 2003, doi:10.1165/rcmb.2002-0310OC Am. J. Respir. Cell Mol. Biol., Volume 29, Number 5, November 2003, 545-551 A more recent version of this article appeared on November 1, 2003
Submitted on December 20, 2002 Apoptosis Genes in Human Alveolar Macrophages Infected with Virulent or Attenuated M. tuberculosisAvrum Spira1,1 Pulmonary Center, Boston University School of Medicine, Boston, MA, USA, 2 Microbiology and Immunology, University of Arkansas, Little Rock, AR, USA, 3 Medicine, University of Massachusetts Medical School, Worchester, MA, USA, 4 Respiratory Medicine, Trinity College Dublin, Dublin, Ireland; Pulmonary Center, Boston University School of Medicine, Boston, MA, USA * To whom correspondence should be addressed. E-mail: jkeane{at}stjames.ie.
Tumor necrosis factor-
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(TNF)-dependent apoptosis of alveolar macrophages after infection with avirulent M. 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 alveolar macrophages. Although we found variation in gene expression between different donors
of alveolar macrophages, a set of genes were constant for each condition. A group of pro-apoptotic genes were down regulated after infection by virulent Mtb strain H37Rv, while 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.
