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.
-
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.
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.
Metrics
-
- 1,244
- views
-
- 193
- downloads
-
- 5
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Candida albicans exhibits heterogeneous and adaptive cytoprotective responses to anti-fungal compounds
eLife 12:e81406.
https://doi.org/10.7554/eLife.81406
Further reading
-
- Computational and Systems Biology
- Neuroscience
The basolateral amygdala (BLA) is a key site where fear learning takes place through synaptic plasticity. Rodent research shows prominent low theta (~3–6 Hz), high theta (~6–12 Hz), and gamma (>30 Hz) rhythms in the BLA local field potential recordings. However, it is not understood what role these rhythms play in supporting the plasticity. Here, we create a biophysically detailed model of the BLA circuit to show that several classes of interneurons (PV, SOM, and VIP) in the BLA can be critically involved in producing the rhythms; these rhythms promote the formation of a dedicated fear circuit shaped through spike-timing-dependent plasticity. Each class of interneurons is necessary for the plasticity. We find that the low theta rhythm is a biomarker of successful fear conditioning. The model makes use of interneurons commonly found in the cortex and, hence, may apply to a wide variety of associative learning situations.
-
- Cancer Biology
- Computational and Systems Biology
Effects from aging in single cells are heterogenous, whereas at the organ- and tissue-levels aging phenotypes tend to appear as stereotypical changes. The mammary epithelium is a bilayer of two major phenotypically and functionally distinct cell lineages: luminal epithelial and myoepithelial cells. Mammary luminal epithelia exhibit substantial stereotypical changes with age that merit attention because these cells are the putative cells-of-origin for breast cancers. We hypothesize that effects from aging that impinge upon maintenance of lineage fidelity increase susceptibility to cancer initiation. We generated and analyzed transcriptomes from primary luminal epithelial and myoepithelial cells from younger <30 (y)ears old and older >55y women. In addition to age-dependent directional changes in gene expression, we observed increased transcriptional variance with age that contributed to genome-wide loss of lineage fidelity. Age-dependent variant responses were common to both lineages, whereas directional changes were almost exclusively detected in luminal epithelia and involved altered regulation of chromatin and genome organizers such as SATB1. Epithelial expression of gap junction protein GJB6 increased with age, and modulation of GJB6 expression in heterochronous co-cultures revealed that it provided a communication conduit from myoepithelial cells that drove directional change in luminal cells. Age-dependent luminal transcriptomes comprised a prominent signal that could be detected in bulk tissue during aging and transition into cancers. A machine learning classifier based on luminal-specific aging distinguished normal from cancer tissue and was highly predictive of breast cancer subtype. We speculate that luminal epithelia are the ultimate site of integration of the variant responses to aging in their surrounding tissue, and that their emergent phenotype both endows cells with the ability to become cancer-cells-of-origin and represents a biosensor that presages cancer susceptibility.
