I

FIG. 3. Kinetics of death of (C3HXB6)F2 mice after intravenous infection with 106 colony-forming units of Mycobacterium tuberculosis in four independent experiments.

Weeks of infection

FIG. 3. Kinetics of death of (C3HXB6)F2 mice after intravenous infection with 106 colony-forming units of Mycobacterium tuberculosis in four independent experiments.

TABLE 1 Linkage of susceptibility to tuberculosis with the marker on chromosome 1 (D1mit49)

Survival

hh

hb

bb

Total

< 8 weeks

73

9

4

86

> 8 weeks

19

149

71

239

Total

92

158

75

325

two groups based on their mortality and homozygosity for the C3H allele on chromosome 1. One group of mice died within four to six weeks and their susceptibility could be explained by homozygosity for the C3H allele on chromosome 1 (the B6 resistant allele is dominant). The mice that died within seven to 10 weeks after infection represent a smaller group and their susceptibility could not be associated with the same locus. Moreover, not every mouse that is homozygous for the C3H allele at chromosome 1 died early after infection; the mice that died within four to six weeks represented 70-80 % of all homozygotes. The incomplete penetrance ofthe chromosome 1 locus suggests that other genes may be influencing the phenotype. Consistent with this is the finding that the majority of the F2 mice which survived the first 10 weeks of infection gradually died within the next three months with fewer than 10% of the animals surviving for as long as the F1 hybrids (the expectation based on the Mendelian distribution for a single autosomal gene would be 75%).

No significant association of early susceptibility with either parental H-2 alleles was detected in our screen. These data do not exclude a role for MHC genes in tuberculosis infection, but would indicate that their phenotypic expression is affected by epistatic interactions with other genetic factors. For example, a role for H-2 in the control of multiplication of M. tuberculosis in chronically infected mice has been reported (Brett et al 1992), but such an effect may be revealed only by determination of the viable bacteria in the lungs of long-term survivors. Finally, our data showed no evidence for a protective effect of the resistant allele of Nrampl, which is another important gene implicated in the control of the multiplication of a number of intracellular pathogens (Skamene et al 1982, Vidal et al 1995, Blackwell 1996). Indeed, C3H mice carry the resistant allele of Nrampl on chromosome 1, but the locus on chromosome 1 identified in our experiments is of C3H origin and confers susceptibility, not resistance. This result suggests that experiments using Bcg congenic strains to study Nrampl activity in M. tuberculosis infection (Medina & North 1996) may be confounded by effects of closely linked genes. The effect of Nrampl might possibly be revealed if its resistant allele, which is present on the chromosome 1 of the C3H

mice (39.2 cM), could be dissociated from the tuberculosis susceptibility locus on the same chromosome (30—70 cM), which was detected in our study. Another intriguing possibility is that the same functional activity of Nrampl that suppresses the multiplication of avirulent BCG could be harmful to the host during the course of infection with the virulent M. tuberculosis. Further genetic studies involving marker-directed backcrosses will be required to distinguish between the two possibilities.

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