Genetic control of resistance to experimental infection with virulentMycobacterium tuberculosis

Over 2 billion people are estimated to be infected with virulentMycobacterium tuberculosis , yet fewer than 10% progress to clinical tuberculosis within their lifetime. Twin studies and variations in the outcome of tuberculosis infection after exposure to similar environmental risks suggest genetic heterogeneity among individuals in their susceptibility to disease. In a mouse model of tuberculosis, we have established that resistance and susceptibility to virulentM. tuberculosis is a complex genetic trait. A new locus with a major effect on tuberculosis susceptibility, designatedsst1 (susceptibility to tuberculosis 1 ), was mapped to a 9-centimorgan (cM) interval on mouse chromosome 1. It is located 10–19 cM distal to a previously identified gene,Nramp1 , that controls the innate resistance of mice to the attenuated bacillus Calmette–Guérin vaccine strain. The phenotypic expression of the newly identified locus is distinct from that ofNramp1 in thatsst1 controls progression of tuberculosis infection in a lung-specific manner. Mice segregating at thesst1 locus exhibit marked differences in the growth rates of virulent tubercle bacilli in the lungs. Lung lesions in congenicsst1 -susceptible mice are characterized by extensive necrosis and unrestricted extracellular multiplication of virulent mycobacteria, whereassst1 -resistant mice develop interstitial granulomas and effectively control multiplication of the bacilli. The resistant allele ofsst1, although powerful in controlling infection, is not sufficient to confer full protection against virulentM. tuberculosis , indicating that other genes located outside of thesst1 locus are likely also to be important for controlling tuberculosis infection.