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  • Review Article
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Genetic susceptibility to infectious disease: lessons from mouse models of leishmaniasis

Nature Reviews Genetics volume 7, pages 294–305 (2006)Cite this article

Key Points

  • Susceptibility to leishmaniasis is influenced by multiple host genes, most of which are low-penetrance QTLs. They have been difficult to map in humans because of their number, the genetic heterogeneity of the population and a range of environmental influences that affect individual risk.

  • This disease can be dissected genetically using mouse models by employing inbred, congenic, recombinant inbred and recombinant congenic strains, and a number of loci and mutant genes that control the response to infection have been described.

  • The most extensive information about the genetics of leishmaniasis in mouse models has been obtained with Leishmania major, studies of which have revealed a multigenic basis of susceptibility, and have led to the mapping of more than 20 QTLs — the L. major response (Lmr) loci.

  • These studies have also revealed the functional heterogeneity of individual genes, and have indicated an organ-specific control of anti-parasite responses. The functional heterogeneity of susceptibility genes has also been described in the response to Borrelia burgdorferi and, to a lesser extent, in other infections, and might be a common characteristic of the host response.

  • Analysis of the response to L. major in 20 recombinant congenic strains has demonstrated that several different functional patterns of immune-response components might be associated with disease or healing, depending on the host genotype. This indicates that susceptibility to L. major is not due to a single mechanism, but rather can result from several different combinations of effects of multiple genes that interact in a functional network.

  • Analysis of the response to L. major showed that when a sufficient number of loci is identified, the disease phenotype can be predicted.

  • The early and later stages of infection with L. donovani are controlled by different genes.

  • Several Lmr loci co-localize with QTLs and influence the response to other infectious agents, including both bacteria and parasites. This indicates that there are clusters of either functionally related genes or genes that control the response to several infections.

  • Overall, genetic studies of susceptibility to leishmaniasis in mice have revealed a network-like complexity for the combined effects of the multiple QTLs that are involved. Therefore, the most important components (genes with the largest effect) might vary, depending on the genotype of the host. This model could become a general paradigm for host responses to infection.

Abstract

Susceptibility to infectious disease is influenced by multiple host genes, most of which are low penetrance QTLs that are difficult to map in humans. Leishmaniasis is a well-studied infectious disease with a variety of symptoms and well-defined immunological features. Mouse models of this disease have revealed more than 20 QTLs as being susceptibility genes, studies of which have made important contributions to our understanding of the host response to infection. The functional effects of individual QTLs differ widely, indicating a networked regulation of these effects. Several of these QTLs probably also influence susceptibility to other infections, indicating that their characterization will contribute to our understanding of susceptibility to infectious disease in general.

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Figure 1: Infection cycle of leishmaniasis.
Figure 2: Loci and genes that control the mouse response to leishmaniasis and other infections.

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Acknowledgements

This work was supported by the Howard Hughes Medical Institute, the Grant Agency of the Czech Republic, the Academy of Sciences of the Czech Republic, Roswell Park Cancer Institute Recruitment/Start-up Funds for New Investigators, a European Commission Contract and a Netherlands Scientific Research Organization Program Grant.

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Authors and Affiliations

  1. Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Fleming. nám. 2, Prague, 166 37, Czech Republic

    Marie Lipoldová

  2. Roswell Park Cancer Institute, Buffalo, 14263, NY, USA

    Peter Demant

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  1. Marie Lipoldová
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  2. Peter Demant
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Correspondence to Marie Lipoldová.

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DATABASES

Entrez Genome Project

Leishmania major

FURTHER INFORMATION

Marie Lipoldová's homepage

WHO Leishmaniasis information

Mouse Genome Informatics

International HapMap Project

Glossary

Penetrance

The degree of effect of a gene on the phenotypes it controls. Low-penetrance disease-susceptibility genes increase the probability of developing a disease, but not all carriers of such genes become affected.

Neutrophils

Circulating phagocytic granulocytes that are involved in the early inflammatory response.

Dendritic cells

Cells that present antigen to T cells, and stimulate cell proliferation and the immune response.

T helper cells

T cells that generally carry CD4 membrane glycoprotein. They secrete numerous cytokines that activate B cells, cytotoxic T cells and macrophages.

Interferon-γ

(IFN-γ). A glycoprotein that is mainly produced by natural killer cells and T helper lymphocytes. It regulates many aspects of the immune response, including induction of antiviral responses, and stimulates macrophages to kill invading pathogens.

Regulatory T cells

Maintain immune tolerance by suppressing the function of T cells, B cells, macrophages, dendritic cells and natural killer cells.

Non-cure response

A response in which an infection fails to heal, but is not necessarily fatal.

New World Leishmania species

Species that originate in South and Central America: Leishmania (Viannia) peruviana, L.(V.) braziliensis, L.(V.) guyanensis, L. amazonensis, L. mexicana and L. chagasi (which is L. infantum that has been brought to the New World only recently).

Old World Leishmania species

Species that inhabit the world that was known to Europeans before the voyages of Columbus, and consist of L. major, L. tropica, L. infantum, L. aethiopica and L. donovani.

Association study

When a genetic variant is genotyped in a population for which phenotypic information is available (such as disease occurrence or a quantitative trait), there is said to be an association between them if a correlation is observed between the phenotype and the variant.

HLA class I and class II molecules

Class I and class II antigens are polymorphic membrane glycoproteins that are encoded by the human MHC and expressed on all nucleated cells and antigen-presenting cells, respectively. They form complexes with antigenic peptides and present them to cytotoxic or T helper cells.

Post-Kala-azar dermal leishmaniasis

Arash that sometimes develops 0.5–13 months following the apparently successful treatment of visceral leishmaniasis. In most cases, it heals spontaneously.

CD3

A membrane-protein complex that is associated with the T-cell receptor and has a role in signal transduction.

Splenomegaly

Enlargement of spleen.

Hepatomegaly

Enlargement of liver.

Inducible nitric oxide synthase

(iNOS). An enzyme that is induced in macrophages by microbial molecules together with T-cell-derived IFN. It produces nitric oxide, a reactive radical with potent antimicrobial activity.

Innate immunity

Non-specific host defences that exist prior to exposure to an antigen, and involve anatomic, physiological, phagocytic and inflammatory mechanisms.

Acquired immunity

Host defences that are mediated by B cells and T cells following exposure to antigen, and that exhibit high levels of specificity and provide an immunological 'memory'.

Haplotype

An experimentally determined profile of genetic markers that are present on a single chromosome of any given individual.

Major histocompatibility complex

(MHC). A complex locus on chromosome 6p in humans and chromosome 17 in mice. It comprises numerous genes, including the class I and class II MHC antigens, that present antigenic peptides to cytotoxic T cells and T-helper cells, respectively. The MHC is essential for development of the acquired immune response.

Antigen presentation

Conversion of protein antigens into MHC-associated peptide fragments that can be recognized by T cells.

Complement

Proteins of the complement pathway coat and lyse invading organisms, and release inflammatory mediators.

Granuloma

A tumour-like mass or nodule that develops due to a chronic inflammatory response. It contains activated macrophages, epithelioid cells (modified macrophages), T cells and multinucleated giant cells that result from the fusion of macrophages.

Natural killer cell

(NK cell). A large granular lymphocyte that has cytotoxic activity but does not express antigen-binding receptors. It exhibits antibody-independent killing of tumour cells, and also participates in antibody-dependent cell-mediated cytotoxicity.

Genetical genomics

A strategy that correlates information on the segregation of genomic regions (in populations or experimental crosses) with gene-expression patterns (in microarray studies). This approach reveals patterns of cis- and trans-regulation of gene expression.

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Lipoldová, M., Demant, P. Genetic susceptibility to infectious disease: lessons from mouse models of leishmaniasis. Nat Rev Genet 7, 294–305 (2006). https://doi.org/10.1038/nrg1832

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