Nonspecific resistance to Mycobacteria: the role of the Nramp1 gene.

The genus Mycobacteria consists of over 50 species that include two of the best-known human pathogens, M. tuberculosis and M. leprae, the causes of tuberculosis (TB) and leprosy, respectively. Whereas the spread of leprosy currently appears to be under control, there are presently about 30 million active cases of TB worldwide, with an alarming increase in the number of multidrug resistant case of M. tuberculosis. As strategies for antibiotic intervention against TB become more limited, it is imperative to develop new therapeutic approaches against this oppressive disease. One promising avenue is to characterize the host genes and gene products which regulate resistance to mycobacterial infections. In the mouse, resistance and susceptibility to intracellular growth of Mycobacteria in macrophages is controlled by the Bcg (Nramp1) gene, which has now been cloned and shown to encode a macrophage transmembrane protein with a putative transporter function. Sequencing of Nramp1 revealed that susceptibility to infection is associates with a single, nonconservative glycine to aspartic acid substitution at position 169 (G169D). Although the intracellular location of the Nramp1 protein in macrophages has not yet been determined, a phagosomal site has been postulated. Consistent with the proposed role of Nramp1 in macrophage activation, recent studies of the Nramp1 promoter region have revealed consensus sequences associated with responsiveness to IFN-gamma and LPS. Finally, a total of 11 polymorphisms have been identified within the human NRAMP1 gene which are being used to test for linkage of NRAMP1 alleles with human susceptibility to TB and leprosy.