Tuberculosis' self-defense

Genes identified that may help Mycobacterium tuberculosis resist host immune system | By Andrea Rinaldi



Tuberculosis is primarily a disease of the respiratory system, with the bacterium being spread in the aerosols generated by coughing and sneezing. The actinomycetous bacteria Mycobacterium tuberculosis is the causative agent and usually resides in the alveolar macrophages. In most people, the bacteria are prevented from growing, but in immunocompetent hosts, mycobacteria infection may persist for decades. Some 2 billion people worldwide are latent tuberculosis carriers and are at risk of developing the disease in the future. In the December 12 Science, K. Heran Darwin and colleagues at the Weill Medical College of Cornell University report the strategies used by the tuberculosis bug to avoid complete destruction by host immune system (Science, 302:1963-1966, December 12, 2003).

Macrophages produce nitric oxide and other reactive nitrogen intermediates (RNIs) that help control, but not eradicate, the tuberculosis infection. Darwin et al. examined the mycobacterial genes required for resistance against RNIs by screening thousands of M. tuberculosis mutants for increased sensitivity to mildly acidified nitrite, used to model exposure to physiological RNIs. The authors identified 12 mutant genes conferring hypersensitivity to RNIs. Of these 12, five encoded putative components of the proteasome, a protein complex that in eukaryotes degrades oxidized or otherwise damaged cytoplasmic proteins, but whose function in prokaryotes has remained unclear. One of the proteasome mutants showed markedly reduced virulence when used to experimentally infect mice. In addition, two chemically distinct proteasome inhibitors sensitized wildtype M. tuberculosis cells to RNIs.

“One function of the bacterial proteasome is to protect the organism against oxidative or nitrosative stress. The mechanism of protection probably involves the degradation of proteins that are irreversibly oxidized, nitrated, or nitrosated,” conclude the authors. Alternatively, the proteasome might repair the proteins damaged by RNIs.

In a related Perspective article, Jean Pieters at the University of Basel and Hidde Ploegh at Harvard Medical School note that although much is still unknown about the mycobacterial proteasome, the findings by Darwin et al. may hold significant therapeutic potential. “Compounds designed to specifically inhibit the mycobacterial proteasome would seem an obvious goal for medicinal chemists aiming to develop new drugs to treat tuberculosis,” they say.