Symptoms of human leishmaniasis range from subclinical to extensive systemic disease with splenomegaly, hepatomegaly, skin lesions, anemia and hyperglobulinemia, but the basis of this variation is unknown. Association of progression of the disease with Th2 lymphocyte response was reported in mice but not in humans. As most genetic studies in Leishmania major (L. major)-infected mice were restricted to skin lesions, we analyzed the symptomatology of leishmaniasis in mice by monitoring skin lesions, hepatomegaly, splenomegaly and seven immunological parameters. We detected and mapped 17 Leishmania major response (Lmr) gene loci that control the symptoms of infection. Surprisingly, the individual Lmr loci control 13 different combinations of pathological and immunological symptoms. Seven loci control both pathological and immunological parameters, 10 influence immunological parameters only. Moreover, the genetics of clinical symptoms is also very heterogeneous: loci Lmr13 and Lmr4 determine skin lesions only, Lmr5 and Lmr10 skin lesions and splenomegaly, Lmr14 and Lmr3 splenomegaly and hepatomegaly, Lmr3 (weakly) skin lesions, and Lmr15 hepatomegaly only. Only two immunological parameters, IgE and interferon-gamma serum levels, correlate partly with clinical manifestations. These findings extend the paradigm for the genetics of host response to infection to include numerous genes, each controlling a different set of organ-specific and systemic effects.

Department of Molecular and Cellular Immunology Institute of Molecular Genetics Academy of Sciences of the Czech Republic Prague Czech Republic

Citace poskytuje Crossref.org

Improving reproducibility and translational potential of mouse models: lessons from studying leishmaniasis

Functionally distinct regions of the locus Leishmania major response 15 control IgE or IFNγ level in addition to skin lesions

Novel Loci Controlling Parasite Load in Organs of Mice Infected With Leishmania major, Their Interactions and Sex Influence

A novel locus on mouse chromosome 7 that influences survival after infection with tick-borne encephalitis virus

Genetic Regulation of Guanylate-Binding Proteins 2b and 5 during Leishmaniasis in Mice

Gene-specific sex effects on eosinophil infiltration in leishmaniasis

Mapping the genes for susceptibility and response to Leishmania tropica in mouse

Mice with different susceptibility to tick-borne encephalitis virus infection show selective neutralizing antibody response and inflammatory reaction in the central nervous system

Genetics of host response to Leishmania tropica in mice - different control of skin pathology, chemokine reaction, and invasion into spleen and liver

Genetic control of resistance to Trypanosoma brucei brucei infection in mice

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