Abstract

Candida albicans, an opportunistic human pathogen, poses a significant threat to human health and is associated with significant socio-economic burden. Current antifungal treatments fail, at least in part, because C. albicans can initiate a strong drug tolerance response that allows some cells to grow at drug concentrations above their minimal inhibitory concentration. To better characterize this cytoprotective tolerance program at the molecular single cell level, we used a nano-liter droplet-based transcriptomics platform to profile thousands of individual fungal cells and establish their subpopulation characteristics in the absence and presence of antifungal drugs. Profiles of untreated cells exhibit heterogeneous expression that correlates with cell cycle stage with distinct metabolic and stress responses. At two days post-fluconazole exposure (a time when tolerance is measurable), surviving cells bifurcate into two major subpopulations: one characterized by the upregulation of genes encoding ribosomal proteins, rRNA processing machinery and mitochondrial cellular respiration capacity, termed the Ribo-dominant (Rd) state; and the other enriched for genes encoding stress responses and related processes, termed the Stress-dominant (Sd) state. This bifurcation persists at 3 and 6 days post treatment. We provide evidence that the Ribosome Assembly Stress Response (RASTR) is activated in these subpopulations and may facilitate cell survival.

Data availability

Python/R code and data required for reproducibility is available through the Open Science Foundation (OSF) repository https://osf.io/5tpk3/ and associated github repository https://github.com/vdumeaux/sc-candida_paper. The raw and processed single-cell transcriptome and bulk RNA-seq is also available through NCBI's Gene Expression Omnibus with accession number GSE204903.

The following data sets were generated

Article and author information

Author details

  1. Vanessa Dumeaux

    Department of Anatomy and Cell Biology, Western University, London, Canada
    For correspondence
    vdumeaux@uwo.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1280-6541
  2. Samira Massahi

    Department of Biology, Concordia University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Van Bettauer

    Department of Computer Science and Software Engineering, Concordia University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Austin Mottola

    Shmunis School of Biomedical and Cancer Research, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Anna Dukovny

    Shmunis School of Biomedical and Cancer Research, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Sanny Singh Khurdia

    Department of Biology, Concordia University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Anna Carolina Borges Pereira Costa

    Department of Biology, Concordia University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  8. Raha Parvizi Omran

    Department of Biology, Concordia University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Shawn Simpson

    Department of Computer Science and Software Engineering, Concordia University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Jinglin Lucy Xie

    Department of Chemical and Systems Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Malcolm Whiteway

    Department of Biology, Concordia University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6619-7983
  12. Judith Berman

    Shmunis School of Biomedical and Cancer Research, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  13. Michael T Hallett

    Department of Biochemistry, Western University, London, Canada
    For correspondence
    michael.hallett@uwo.ca
    Competing interests
    The authors declare that no competing interests exist.

Funding

Natural Sciences and Engineering Research Council of Canada (RGPIN-2018-05085)

  • Michael T Hallett

Canada Foundation for Innovation (37083)

  • Michael T Hallett

European Research Council (951475)

  • Judith Berman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2023, Dumeaux et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Vanessa Dumeaux
  2. Samira Massahi
  3. Van Bettauer
  4. Austin Mottola
  5. Anna Dukovny
  6. Sanny Singh Khurdia
  7. Anna Carolina Borges Pereira Costa
  8. Raha Parvizi Omran
  9. Shawn Simpson
  10. Jinglin Lucy Xie
  11. Malcolm Whiteway
  12. Judith Berman
  13. Michael T Hallett
(2023)
Candida albicans exhibits heterogeneous and adaptive cytoprotective responses to anti-fungal compounds
eLife 12:e81406.
https://doi.org/10.7554/eLife.81406

Share this article

https://doi.org/10.7554/eLife.81406

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