Resistance to Leishmania major is linked to the H2 region on chromosome 17 and to chromosome 9

Abstract

In Leishmaniasis, as in many infectious diseases, clinical manifestations are determined by the interaction between the genetics of the host and of the parasite. Here we describe studies mapping two loci controlling resistance to murine cutaneous leishmaniasis. Mice infected with L. major show marked genetic differences in disease manifestations: BALB/c mice are susceptible, exhibiting enlarging lesions that progress to systemic disease and death, whereas C57BL/6 are resistant, developing small, self-healing lesions. F2 animals from a C57BL/6 X BALB/c cross showed a continuous distribution of lesion score. Quantitative trait loci (QTL) have been mapped after a non-parametric QTL analysis on a genome-wide scan on 199 animals. QTLs identified were confirmed in a second cross of 271 animals. Linkage was confirmed to a chromosome 9 locus (D9Mit67-D9Mit71) and to a region including the H2 locus on chromosome 17. These have been named Imr2 and Imr1, respectively.

Figure 1

The kinetics of lesion development after L. major infection in BALB/c, C57BL/6, and their F1 generation expressed as the median lesion score over time. A shows results from 12 BALB/c, 12 C57BL/6, and 24 F1 mice. B shows the second experiment with 16 BALB/c, 6 C57BL/6, and 12 F1 mice. The vertical bars represent the semi-interquartile ranges. As all C57BL/6 mice cure their lesions, resistance is fully penetrant.

Figure 2

The kinetics of lesion development after L. major infection in the F2 generation expressed as the lesion score over time. A and B represent two separate experiments with 199 and 271 F2 mice, respectively. The first quartile represents the lesion score of the animal at the 25th percentile, the second quartile represents the 50th percentile animal, etc. These data demonstrate a continuous distribution of this trait in the F2 generation. Animals were slightly more resistant in the second experiment compared to the first.

Figure 3

A 12 cM density genome-wide non-parametric QTL scan for outcome of L. major infection in 199 F2 mice. The results are expressed as the non-parametric X_w score. Linkage is considered significant at the threshold of 4.4, which is equivalent to a lod score of 3.3. Chr. = Chromosome.