Candida albicans exhibits heterogeneous and adaptive cytoprotective responses to anti-fungal compounds
- Western University, Canada
- Concordia University, Canada
- Tel Aviv University, Israel
- Stanford University, United States
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.
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Candida albicans exhibits heterogeneous and adaptive cytoprotective responses to anti-fungal compoundsNCBI Gene Expression Omnibus, GSE204903.
Article and author information
Author details
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.
Reviewing Editor
- Antonis Rokas, Vanderbilt University, United States
Version history
- Received: June 25, 2022
- Preprint posted: July 21, 2022 (view preprint)
- Accepted: October 26, 2023
- Accepted Manuscript published: October 27, 2023 (version 1)
- Version of Record published: December 6, 2023 (version 2)
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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Candida albicans exhibits heterogeneous and adaptive cytoprotective responses to anti-fungal compounds
eLife 12:e81406.
https://doi.org/10.7554/eLife.81406
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