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Single nucleotide polymorphisms are associated with strain-specific virulence differences among clinical isolates of Cryptococcus neoformans

Author

Listed:
  • Katrina M. Jackson

    (University of Minnesota
    Northern Arizona University)

  • Thomas J. Y. Kono

    (University of Minnesota
    University of Cologne)

  • Jovany J. Betancourt

    (University of Minnesota)

  • Yina Wang

    (Rutgers University)

  • Kisakye D. Kabbale

    (Makerere University
    The African Center of Excellence in Bioinformatics and Data Intensive Sciences)

  • Minna Ding

    (University of Minnesota)

  • Perry Kezh

    (Virginia Tech University)

  • Grace Ha

    (University of Minnesota)

  • J. Marina Yoder

    (University of Minnesota)

  • Sophie R. Fulton

    (University of Minnesota)

  • Liliane Mukaremera

    (Medical Research Council Centre for Medical Mycology at the University of Exeter)

  • Peter Tiffin

    (University of Minnesota)

  • Asiya Gusa

    (Duke University)

  • David B. Meya

    (Makerere University
    University of Minnesota)

  • R. Blake Billmyre

    (University of Georgia)

  • Chaoyang Xue

    (Rutgers University)

  • Kirsten Nielsen

    (University of Minnesota
    Virginia Tech University)

Abstract

Studies across various pathogens highlight the importance of pathogen genetic differences in disease manifestation. In the human fungal pathogen Cryptococcus neoformans, sequence type (ST) associates with patient outcome. We performed a meta-analysis of four genomic studies and identified overlapping gene regions associated with virulence, suggesting the importance of these gene regions in cryptococcal disease in diverse clinical isolates. We explored the relationship between virulence and strain genetic differences using the cryptococcosis mouse model and a closely related library of ST93 clinical isolates. We identified four in vivo virulence phenotypes: hypervirulence, typical virulence with CNS disease, typical virulence with non-CNS disease, and latent disease. Hypervirulent isolates were clade specific and associated with an interferon gamma (IFNγ) dominated immune response. Using a genome wide association study (GWAS), we identified nine genes with polymorphisms associated with IFNγ production, including the inositol sensor ITR4. The itr4Δ mutant recapitulated the hypervirulence phenotype and ITR4 affects expression of two IFNγ associated genes. Finally, we showed that IFNγ production is associated with SNPs that downregulate ITR4 and with SNP accumulation in other IFNγ associated genes. These data highlight the complex role of pathogen genetics in virulence and identify genes associated with hypervirulence and IFNγ in Cryptococcus neoformans.

Suggested Citation

  • Katrina M. Jackson & Thomas J. Y. Kono & Jovany J. Betancourt & Yina Wang & Kisakye D. Kabbale & Minna Ding & Perry Kezh & Grace Ha & J. Marina Yoder & Sophie R. Fulton & Liliane Mukaremera & Peter Ti, 2024. "Single nucleotide polymorphisms are associated with strain-specific virulence differences among clinical isolates of Cryptococcus neoformans," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54729-6
    DOI: 10.1038/s41467-024-54729-6
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    References listed on IDEAS

    as
    1. Robert Tibshirani & Guenther Walther & Trevor Hastie, 2001. "Estimating the number of clusters in a data set via the gap statistic," Journal of the Royal Statistical Society Series B, Royal Statistical Society, vol. 63(2), pages 411-423.
    2. Jae-Hyung Jin & Kyung-Tae Lee & Joohyeon Hong & Dongpil Lee & Eun-Ha Jang & Jin-Young Kim & Yeonseon Lee & Seung-Heon Lee & Yee-Seul So & Kwang-Woo Jung & Dong-Gi Lee & Eunji Jeong & Minjae Lee & Yu-B, 2020. "Genome-wide functional analysis of phosphatases in the pathogenic fungus Cryptococcus neoformans," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
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