Mouse genetic model for clinical and immunological heterogeneity of leishmaniasis

Abstract

Systematic assessment of the role of host genes in clinico-pathological and immunological manifestations of Leishmania major-induced disease in mice was performed using 20 recombinant congenic (RC) strains. As the RC strains are homozygous and each carries a different, random set of 12.5% genes from the resistant strain, STS/A, and 87.5% genes from the susceptible strain, BALB/cHeA, they allowed us to study the pathological and immunological characteristics of infected hosts in 20 fixed different random combinations of BALB/c and STS genes. The 20 RC strains differ widely in expression of different symptoms of disease and in immunological characteristics. Disease or healing in different strains occurred in association with different components of immune response -- with the exception of a frequently occurring correlation between the disease and IgE levels. Moreover, some parameters of the immune response were highly correlated in some strains but not at all in others. This shows that several patterns of the immune response may be associated with the same clinical outcome, depending on the host genotype. Our data also suggest that despite the complexity of regulation, when a sufficient number of controlling loci is known, the prediction of a phenotype is possible. Combining functional and clinical information with multilocus genotyping may improve our ability to predict the progression of the disease and to optimize the treatment.

Genetics of susceptibility to leishmaniasis in mice: four novel loci and functional heterogeneity of gene effects

“…When infected by L. major, the CcS strains exhibited a continuous range of susceptibility (measured by the extent of skin lesions) demonstrating that the susceptibility is indeed multigenically controlled. 22 Our investigation whether the development of skin lesions in individual RC strains correlates with other pathological characteristics and immunological parameters led to surprising results: they have been correlated in some cases (skin lesion size correlated with splenomegaly, r ¼ 0.62, and with parasite load in lymph nodes, r ¼ 0.70) although there was no correlation between splenomegaly and load of parasites in spleen. Interleukin-4 and IFN-g levels were strongly correlated (r ¼ 0.74) and a similar correlation has been suggested in human leishmaniasis patients.…”

“…These data indicated that different pathological and immunological traits are largely controlled by different sets of genes that only partly overlap. 22 However, this notion needs to be rigorously examined by detection and mapping of individual genes controlling various symptoms of the disease. This evidence is given in the present paper.…”

Mouse genetic model for antigen-induced airway manifestations of asthma

“…17 This series of RC strains has been used to dissect the genetics of T-cell activation and several models of inflammatory diseases, including Mycobacterium tuberculosis and L. major infection. 17,[19][20][21][22][23][24][25]27 In the present study, we used the CcS/Dem series to determine the susceptibility of each strain and both parental strains BALB/cHeA and STS/A for antigeninduced airway manifestations of asthma as described by Deurloo et al 34 Generated data were used to calculate correlations between the different asthma-related characteristics for all individual strains and in the pooled population.…”

“…18 In several diseases, the recombinant congenic (RC) strains of mice have proven to be a powerful tool to provide the mapping of genes controlling complex traits. 17,[19][20][21][22][23][24][25][26][27] A series of RC strains comprises approximately 20 homozygous strains, each of which contains on average 87.5% genes of a common background strain and 12.5% of a common donor strain. 26,28 In this way, the RC system transforms a multigenic difference into a set of mono-or oligogenic differences and hence offers higher resolution power in mapping the quantitative trait loci and detecting their mutual interactions than the standard genetic methods.…”

Infectious disease — a genetic view

“…These genetic studies have used several model systems, which include comparisons of two or more inbred strains [111][112][113], congenic strains [114,115], recombinant inbred strains [115] and recombinant congenic strains [116][117][118][119][120]. Genetic studies, especially those using recombinant congenic strains, led to a dissociation of correlated phenotypes, and showed that disease or healing in different strains occurs in association with different components of the immune response [121]. This research also revealed a multigenic basis of susceptibility by mapping of more than 20 quantitative trait loci (QTLs) -Lmr -Leishmania major response loci ( Table 2).…”