Editors' ChoiceTuberculosis

It Just Keeps Going and Going

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Science Translational Medicine  23 Feb 2011:
Vol. 3, Issue 71, pp. 71ec22
DOI: 10.1126/scitranslmed.3002274

Some things, like the Energizer Bunny, just can’t be stopped no matter how hard you try. One such indefatigable plague is tuberculosis, which has been afflicting humans for at least 18,000 years. Despite recent medical advances and refocused effort on developing a better vaccine, tuberculosis is thought to infect up to one-third of the world’s population, with devastating results in HIV-infected and other immune-compromised populations. One major hurdle to progress in the treatment and prevention of tuberculosis is the lack of precise understanding of the mechanisms behind the bug’s pathogenesis and ability to evade the immune response. Now, Bustamante and colleagues uncover a mechanistic clue to the pathogen's prodigious success.

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare syndrome that predisposes affected individuals to infection by even weakly virulent mycobacterial species, including bacillus Calmette-Guerin (BCG), which is frequently used as a vaccine for Mycobacterium tuberculosis (MTb). Bustamonte and colleagues identified mutations in the CYBB gene as a contributory factor to MSMD in human patients. CYBB encodes a subunit of reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, an enzyme in phagocytic white blood cells that generates bacteria-killing superoxide. The authors found that these CYBB mutations resulted in a macrophage-specific deficit in respiratory burst by preventing the assembly of NAPDH oxidase. BCG growth was enhanced in macrophages with this defect in vitro, which in conjunction with the MSMD association suggests that respiratory burst probably contributes critically to mycobacterial defense. These data may provide a basis for new treatment strategies to stop this seemingly unstoppable disease.

J. Bustamante et al., Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease. Nat. Immunol. 12, 213–221 (2011). [Abstract]

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