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Sex differences in the genetic architecture of susceptibility to Cryptococcus neoformans pulmonary infection

Genes & Immunity volume 9, pages 536–545 (2008)Cite this article

Abstract

Cryptococcus neoformans is a major cause of fungal pneumonia, meningitis and disseminated disease in the immune compromised host. Here we have used a clinically relevant model to investigate the genetic determinants of susceptibility to progressive cryptococcal pneumonia in C57BL/6J and CBA/J inbred mice. At 5 weeks after infection, the lung fungal burden was over 1000-fold higher in C57BL/6J compared to CBA/J mice. A genome-wide scan performed on 210 male and 203 female (CBA/J × C57BL/6J) F2 progeny using lung colony-forming units as a quantitative trait revealed a sex difference in genetic architecture with three loci (designated Cnes1–Cnes3) associated with susceptibility to cryptococcal pneumonia. Single locus analysis identified significant loci on chromosomes 3 (Cnes1) and 17 (Cnes2) with logarithm of the odds (LOD) scores of 4.09 (P=0.0110) and 7.30 (P<0.0001) that explained 8.9 and 15.9% of the phenotypic variance, respectively, in female CBAB6F2 and one significant locus on chromosome 17 (Cnes3) with a LOD score of 4.04 (P=0.010) that explained 8.6% of the phenotypic variance in male CBAB6F2 mice. Genome-wide pair-wise analysis revealed significant quantitative trait locus interactions in both the female and male CBAB6F2 progeny that collectively explained 43.8 and 19.5% of phenotypic variance in each sex, respectively.

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Acknowledgements

We thank Genevieve Houde for excellent technical assistance, Sean Wiltshire for helpful assistance with the software package R/qtl, and Dr Qutayba Hamid for providing us with microscopy facilities. Grant support was provided by the Research Institute of the McGill University Health Centre, the Canadian Institutes of Health Research (SQ), a Canada Research Chair (SQ), the Career Awards in the Biomedical Sciences program of the Burroughs Wellcome Fund (SQ), the Mathematics of Information Technology and Complex Systems (MITACS) through the Canadian Network of Centres of Excellence Program (JCL-O, KM), and the National Sciences and Engineering Research Council of Canada (JCL-O).

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Authors and Affiliations

  1. Centre for the Study of Host Resistance, McGill University, Montreal, Quebec, Canada

    S F Carroll, L Guillot, K Morgan & S T Qureshi

  2. Department of Human Genetics, McGill University, Montreal, Quebec, Canada

    S F Carroll & K Morgan

  3. Department of Mathematics and Statistics, Memorial University, St John's Newfoundland and Labrador, Canada

    J C Loredo Osti

  4. Department of Medicine, Montreal General Hospital, McGill University, Montreal, Quebec, Canada

    K Morgan & S T Qureshi

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Correspondence to S T Qureshi.

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Carroll, S., Loredo Osti, J., Guillot, L. et al. Sex differences in the genetic architecture of susceptibility to Cryptococcus neoformans pulmonary infection. Genes Immun 9, 536–545 (2008). https://doi.org/10.1038/gene.2008.48

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