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Genetic architecture of tuberculosis resistance in a mouse model of infection

Genes & Immunity volume 7, pages 201–210 (2006)Cite this article

Abstract

Tuberculosis remains a significant public health problem: one-third of the human population is infected with virulent Mycobacterium tuberculosis (MTB) and 10% of those are at risk of developing tuberculosis during their lifetime. In both humans and experimental animal models, genetic variation among infected individuals contributes to the outcome of infection. However, in immunocompetent individuals (the majority of patients), genetic determinants of susceptibility to tuberculosis remain largely unknown. Mouse models of MTB infection, allowing control of exposure and other potential environmental contributors, have proven extremely useful for examining this genetic component. In a cross of C3HeB/FeJ (susceptible) by C57BL/6J (resistant) inbred mouse strains, we have previously identified one major genetic locus, sst1, the susceptible allele of which did not confer an overt immunodeficiency, but rather specifically affected progression of lung tuberculosis. Having generated and tested the sst1 congenic strains, we have observed that this locus only partially explained the difference in susceptibility of the parental strains to MTB. We now present further studies controlling for the effect of the sst1, identify four additional tuberculosis susceptibility loci and characterize their effects by testing an independent cross, knockout or congenic mice.

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Acknowledgements

We gratefully acknowledge Marshfield Center for Medical Genetics at the Marshfield Medical Research Foundation (Marshfield, WI, USA) for performing the whole genome scan. We are also grateful to Ilona Breiterene and Christina Mottley for expert technical assistance. This work was supported by NIH HLBI (Grant R01 HL 059836 to IK).

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Author notes

  1. Y V Shebzukhov

    Present address: Department of Molecular Immunology, AN Belozersky Institute of Physical and Chemical Biology, Moscow State University, Vorobjovy Gory, Moscow, 119899, Russia

  2. M J Daly and I Kramnik: These authors share senior authorship.

Authors and Affiliations

  1. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA

    B-S Yan, Y V Shebzukhov & I Kramnik

  2. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA

    A Kirby & M J Daly

  3. Broad Institute of Harvard and MIT, Cambridge, MA, USA

    M J Daly

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  1. B-S Yan
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Corresponding author

Correspondence to I Kramnik.

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Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

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Yan, BS., Kirby, A., Shebzukhov, Y. et al. Genetic architecture of tuberculosis resistance in a mouse model of infection. Genes Immun 7, 201–210 (2006). https://doi.org/10.1038/sj.gene.6364288

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