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

Genes & Immunity volume 7, pages 220–233 (2006)Cite this article

Abstract

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-γ 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.

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Acknowledgements

This investigation received financial support from the Howard Hughes Medical Institute (Grant 55000323), the Grant Agency of the Czech Republic (Grants 310/03/1381 and 310/03/H147), Academy of Sciences of the Czech Republic (Project no. AVOZ50520514) and from the European Commission (the Contracts ERBI-C15-CT98-0317 and BIO-4-CT98-0445) and from Health Research Inc. (Buffalo, NY, USA). We thank Dr Brian Bundy (Department of Biostatistics, Roswell Park Cancer Institute) for advice on statistical analysis. We acknowledge the permission of Dr P Kodym and Dr K Zitek (State Institute for Health, Prague) to use their laboratory and animal facilities for part of these experiments. We thank Mrs Mary Ketchum for the help with preparation of illustrations.

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  1. V Vladimirov

    Present address: Virginia Institute of Psychiatric and Behavioral Genetics, 800 East Leigh Street, Richmond, VA, 23219, USA

Authors and Affiliations

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

    H Havelková, J Badalová, J Vojtíková, I Kurey, V Vladimirov & M Lipoldová

  2. Center of Biomedical Sciences, Third Faculty of Medicine, Charles University, Prague, Czech Republic

    J Badalová, I Kurey & M Lipoldová

  3. Department of Parasitology, Faculty of Science, Charles University, Prague, Czech Republic

    M Svobodová

  4. Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo,, NY, USA

    P Demant

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Havelková, H., Badalová, J., Svobodová, M. et al. Genetics of susceptibility to leishmaniasis in mice: four novel loci and functional heterogeneity of gene effects. Genes Immun 7, 220–233 (2006). https://doi.org/10.1038/sj.gene.6364290

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