Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis

Over 2 billion people are estimated to be infected with virulent Mycobacter ium tuberculosis, yet fewer than 10% progress to clinical tuberculosis with in their lifetime. Twin studies and variations in the outcome of tuberculos is infection after exposure to similar environmental risks suggest genetic heterogeneity among individuals in their susceptibility to disease. In a mo use model of tuberculosis, we have established that resistance and suscepti bility to virulent M. tuberculosis is a complex genetic trait. A new locus with a major effect on tuberculosis susceptibility, designated sst1 (suscep tibility 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 identifi ed gene, Nramp1. that controls the innate resistance of mice to the attenua ted bacillus Calmette-Guerin vaccine strain. The phenotypic expression of t he newly identified locus is distinct from that of Nramp1 in that sst1 cont rols progression of tuberculosis infection in a lung-specific manner. Mice segregating at the sst1 locus exhibit marked differences in the growth rate s of virulent tubercle bacilli in the lungs. Lung lesions in congenic sst1- susceptible mice are characterized by extensive necrosis and unrestricted e xtracellular multiplication of virulent mycobacteria, whereas sst1-resistan t mice develop interstitial granulomas and effectively control multiplicati on of the bacilli. The resistant allele of sst1, although powerful in contr olling infection, is not sufficient to confer full protection against virul ent M. tuberculosis. indicating that other genes located outside of the sst 1 locus are likely also to he important for controlling tuberculosis infect ion.