The first genetic resistance factor for tuberculosis (TB) infection is now reported by Cobat et al. The group has identified one locus that determines whether an individual will respond to the TB skin test and a second that controls the extent of that response. The results suggest that one major genetic locus controls innate resistance to the pathogen in humans.

Two-thirds of the global population is infected with Mycobacterium tuberculosis, the agent responsible for TB. Yet the disease only manifests in about 10% of infected individuals. To find genetic variants controlling susceptibility to infection, the authors studied 128 families in Cape Town, South Africa, where TB is highly endemic.

Although most subjects were likely to have been exposed to M. tuberculosis, about 40% did not show delayed type hypersensitivity (DTH) in a skin antigen test. This strong resistance mapped to a 6-Mbp chromosome region, 11p14. This locus may unveil cellular mechanisms that might one day be manipulated to prevent TB—an important goal given the recent rise in drug-resistant strains.

The second locus, in the 2.9-Mbp 5p15 region, segregated with differing extents of positive DTH responses. These genetic factors might contribute to whether an infected individual keeps the bacterium dormant or develops the disease. The same chromosomal region is associated with susceptibility to sarcoidosis, an immune disorder of persistent inflammation that is often associated with TB.

A candidate 5p15 gene is a solute carrier (SLC) family member. A human SLC member called NRAMP1 is known to influence granuloma responses to mycobacteria, and loss of the mouse SLC6A3 protein reduces DTH response to ovalbumin. NL