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Investigation of the basis of virulence in serotype A strains of Cryptococcus neoformans from apparently immunocompetent individuals

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Abstract

Cryptococcus neoformans serotype A strains commonly infect immunocompromised patients to cause fungal meningitis. To understand the basis of serotype A cryptococcal infections in apparently immunocompetent patients, we tested two hypotheses: the strains were naturally occurring hypervirulent pkr1 (PKA regulatory subunit) mutants, or the strains were hybrids with C. neoformans var. gattii strains that normally infect immunocompetent individuals. Analysis of clinical isolates obtained from apparently immunocompetent individuals from three continents revealed that none were pkr1 mutants, but several exhibited phenotypes consistent with perturbations in cAMP signaling. Additionally, none of the strains were unusual hybrids with gattii strains. Except for one strain that was an AD hybrid, all others were serotype A (var. grubii) isolates. Taken together, our findings indicate that the ability of these clinical isolates to infect apparently normal individuals may be attributable to mutations other than pkr1 and/or underlying immune system impairment in patients.

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Acknowledgements

We thank Jim Kronstad and John Perfect for advice and comments on the manuscript, Cristl Arndt for technical assistance, and John Bennett, Wieland Meyer, Eric Jacobson, Barbara Alexander-Lodge, and Tom Harrison for strains. This work was supported by NIAID R01 grants AI39115 and AI42159 (to J.H.). This work was also supported by P01 award AI44975 from the NIAID to the Duke University Mycology Research Unit. J.H. is a Burroughs Wellcome Scholar in Molecular Pathogenic Mycology and an associate investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA

    Cletus A. D’Souza, Gary M. Cox & Joseph Heitman

  2. CBS—Centraalbureau voor Schimmelcultures, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands

    Ferry Hagen & Teun Boekhout

  3. Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA

    Gary M. Cox & Joseph Heitman

  4. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA

    Joseph Heitman

  5. The Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA

    Joseph Heitman

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  1. Cletus A. D’Souza
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  2. Ferry Hagen
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  3. Teun Boekhout
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  4. Gary M. Cox
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  5. Joseph Heitman
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Corresponding author

Correspondence to Joseph Heitman.

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Communicated by S. Hohmann

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D’Souza, C.A., Hagen, F., Boekhout, T. et al. Investigation of the basis of virulence in serotype A strains of Cryptococcus neoformans from apparently immunocompetent individuals. Curr Genet 46, 92–102 (2004). https://doi.org/10.1007/s00294-004-0511-y

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  • DOI: https://doi.org/10.1007/s00294-004-0511-y

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