Complex genetic control of susceptibility to Mycobacterium bovis (Bacille Calmette-Guerin) infection in wild-derived Mus spretus mice

Susceptibility to Mycobacterium bovis Bacille Calmette-Guerin (BCG) is genetically controlled by Nramp1 (Slc11a1). Inbred mouse strains harbor either the resistance (Nramp1(G169)) or the susceptibility (Nramp1(D169)) allele at Nramp1. Mus spretus (Nramp1G169; SPRET/EiJ) is shown to display an intermediate level of BCG replication in the spleen (log(10) colony-forming units (CFU)similar to 5), compared to resistant A/J (log(10)CFU similar to 4.0) and susceptible C57BL/6J (log(10)CFU similar to 6.0) mice. The presence of genetic modifiers of Nramp1-dependent susceptibility to M. bovis (BCG) infection in Mus spretus was analyzed by whole-genome scanning in 175 mice of an informative (C57BL/6J x SPRET/EiJ) x C57BL/6J backcross. Nramp1 showed a major effect (D1Mcg4, P < 1e(-4)), but additional single marker effects were identified on chromosomes 4 (D4Mit150) and x (DXMit249) in male mice, and on chromosome 9 (D9Mit77) and 17 (D17Mit81) in female mice. A strong interaction between Nramp1 and the major histocompatibility locus was also noted in female mice. The mapped loci may act as modifiers of Nramp1 action, and constitute novel entry points for the parallel search of loci regulating susceptibility to mycobacterial infections in humans.