Distinct genetic control of parasite elimination, dissemination, and disease after Leishmania major infection

Abstract

Elimination of pathogens is the basis of host resistance to infections; however, relationship between persisting pathogens and disease has not been clarified. Leishmania major infection in mice is an important model of host-pathogen relationship. Infected BALB/c mice exhibit high parasite numbers in lymph nodes and spleens, and a chronic disease with skin lesions, splenomegaly, and hepatomegaly, increased serum IgE levels and cytokine imbalance. Although numerous gene loci affecting these disease symptoms have been reported, genes controlling parasites' elimination or dissemination have never been mapped. We therefore compared genetics of the clinical and immunologic symptomatology with parasite load in (BALB/c×CcS-11) F 2 hybrids and mapped five loci, two of which control parasite elimination or dissemination. Lmr5 influences parasite loads in spleens (and skin lesions, splenomegaly, and serum IgE, IL-4, and IFNγ levels), and Lmr20 determines parasite numbers in draining lymph nodes (and serum levels of IgE and IFNγ), but no skin or visceral pathology. Three additional loci do not affect parasite numbers but influence significantly the disease phenotype-Lmr21: skin lesions and IFNγ levels, Lmr22: IL-4 levels, Lmr23: IFNγ levels, indicating that development of L. major-caused disease includes critical regulations additional to control of parasite spread.

Gene-specific sex effects on eosinophil infiltration in leishmaniasis

“…Experimental data have shown different sex influence on susceptibility to relatively closely related pathogen species [20, 21], different sex biases in susceptibility to the same Leishmania species in different host genotypes [21, 22], and different sex and genetic influence on organ-specific pathology [21, 23, 24]. For example, high resistance to skin lesions induced by L. mexicana was observed in females but not in males of DBA/2 mice, but the sex effect was opposite in L. major infection [20].…”

“…Genotype influence on sex differences was defined in the studies of L. major infection [22, 24]. Giannini [22] found no sex effect on L. major -induced skin pathology and mortality in BALB/cJ mice, but a higher susceptibility of B10.129(10M)ScSn females than males.…”

“…Giannini [22] found no sex effect on L. major -induced skin pathology and mortality in BALB/cJ mice, but a higher susceptibility of B10.129(10M)ScSn females than males. The comparison of L. major susceptibility in two strains, BALB/cHeA and CcS-11 [24], has shown that there is no significant sex influence on skin lesion development, splenomegaly, and hepatomegaly in these strains. However, parasite numbers in lymph nodes are higher in both BALB/c and CcS-11 males; moreover, CcS-11 males have higher parasite load in spleens, showing an organ-specific, sex-, and genotype-dependent pathology [24].…”

Infectious disease — a genetic view

“…Studies using mouse models have revealed functional heterogeneity of individual susceptibility genes, and indicate organ specific control of the antiparasite response [117,119,120]. Moreover, parasite elimination, as well as immunological and pathological processes, are under independent regulation [118]. A combination of recombinant mapping in combination with advanced tools of system genetics led to the identification of a potential candidate gene Fli1 (Friend leukemia integration 1) for Lmr2 [122], which uncovered a novel mechanism in the control of leishmaniasis.…”

“…The most extensive information about the genetics of leishmaniasis in mouse models has been obtained with Leishmania major. 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].…”