Experiment
L. tropica causes cutaneous leishmaniasis in humans and it can also visceralize. Experiments with mice revealed that manifestations of the disease after infection with L. tropica were strongly influenced by the geneotype of the host.
Mice from recombinant congenic strain CcS16, derived from a BALB/c-c-STS/A (CcS/Dem) panel, were crossed with BALB/c mice to create two experimental groups. The CcS16 strain carries 12.5% genes from the resistant parental STS/A strain and 87.5% from the susceptible BALB/c strain and is more susceptible to L. tropica than BALB/c mice. CcS16 was in more than 90 generations of inbreeding when used for these experiments.
The first experiment consisted of 111 mice, 51 mice from a (BALB/c x CcS16)F2 cross and 60 mice from the recprical cross, (CcS16 x BALB/c)F2. The second group contained a total of 134 mice, 64 from a (BALB/c x CcS16)F2 cross and 70 mice from the (CcS16 x BALB/c)F2 cross. Both F2 hybrid groups were derived from the same F1 parents. Infected mice from both experimental groups were genotyped and their linkage with pathological symptoms and systemic immune responses were determined, revealing eight Ltrp (Leishmania tropica response) loci. These loci are functionally heterogeneous - each influences a different set of responses to the pathogen.
Ltpr8, Leishmania tropica response 8, was identified in both crosses as a significant locus in two main effect loci and in two different interactions on Chr 18 with marker D18Mit40 at 37.11 cM and with marker D18Mit49 at 51.27 cM.
02.17.2016 Curator Note: We have retained the broader QTL identified in this study as Ltpr8. We have also assigned official nomenclature to each of the independent traits that map with significance within the broader Ltpr8 locus creating Ltpr8a, Ltpr8b, Ltpr8c and Ltpr8d.
Ltpr8a is a main effect QTL mapping to D18Mit49, corrected p=0.012. A larger spleen to body weight ratio is assciated with the BALB/c allele at this locus measured at week 43, accounting for 18.59% of trait variance. [Table 2.]
Ltpr8b is a main effects QTL mapping with D18Mit40, corrected p=0.013, influencing CCL7 serum levels after 7 weeks of infection. Homozygous BALB/c alleles at this locus are asociated with higher level of CCL7. Ltpr8b accounts for 11.38% of trait variance. [Table 5.]
Ltpr8c, at D18Mit49, was identified in interaction with Ltpr5b at D10Mit103, corrected p=0.029. F2 mice with homozygous STS/A alleles at both Ltpr8c and Ltpr5b have the smallest splenomegaly at week 43 after infection. This interaction accounts for 6.78% of trait variance. [Table 3.]
Ltpr8d, at D18Mit40, was identified in interaction with Ltpr4c at D4Mit153, corrected p=0.021. F2 mice with homozygous BALB/c alleles at Ltpr4c and heterozygous alleles at Ltpr8d have the highest parasite burden in liver after 43 weeks of infection. This interaction explained 8.11% of trait variance. [Table 4.]
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