Abstract
Most microbes have developed responses that protect them against stresses relevant to their niches. Some that inhabit reasonably predictable environments have evolved anticipatory responses that protect against impending stresses that are likely to be encountered in their niches-termed "adaptive prediction". Unlike yeasts such as Saccharomyces cerevisiae, Kluyveromyces lactis and Yarrowia lipolytica and other pathogenic Candida species we examined, the major fungal pathogen of humans, Candida albicans, activates an oxidative stress response following exposure to physiological glucose levels before an oxidative stress is even encountered. Why? Using competition assays with isogenic barcoded strains, we show that "glucose-enhanced oxidative stress resistance" phenotype enhances the fitness of C. albicans during neutrophil attack and during systemic infection in mice. This anticipatory response is dependent on glucose signalling rather than glucose metabolism. Our analysis of C. albicans signalling mutants reveals that the phenotype is not dependent on the sugar receptor repressor pathway, but is modulated by the glucose repression pathway and down-regulated by the cyclic AMP-protein kinase A pathway. Changes in catalase or glutathione levels do not correlate with the phenotype, but resistance to hydrogen peroxide is dependent on glucose-enhanced trehalose accumulation. The data suggest that the evolution of this anticipatory response has involved the recruitment of conserved signalling pathways and downstream cellular responses, and that this phenotype protects C. albicans from innate immune killing, thereby promoting the fitness of C. albicans in host niches.
| Original language | English |
|---|---|
| Pages (from-to) | e1011505 |
| Journal | PLoS Pathogens |
| Volume | 19 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 10 Jul 2023 |
Bibliographical note
AcknowledgmentsWe thank Carol Munro for her generosity in providing the plasmids for barcoding C. albicans, and Victoria Brown, Gerry Fink, Bill Fonzi, Guanghua Huang, Joachim Morschauser, Suzanne Noble, Jesus Pla, Patrick Van Dijck, Reinhard Würzner and Oscar Zaragoza for providing strains. We thank our colleagues in the MRC Centre for Medical Mycology and the Aberdeen Fungal Group for insightful discussions. We are grateful to the following Research Facilities for their advice and support: the Centre for Genome Enabled Biology at the University of Aberdeen, and the Sequencing Facility at the University of Exeter for help with the barcode sequencing.
Funding: This work was funded by a programme grant to AJPB, NARG, LEP and MGN from the UK Medical Research Council [www.mrc.ac.uk: MR/M026663/1, MR/M026663/2] and by PhD studentships to DEL from the Universities of Aberdeen and Exeter. The work was also supported by the Medical Research Council Centre for Medical Mycology (MR/N006364/1, MR/N006364/2). NARG acknowledges Wellcome support of Senior Investigator (101873/Z/13/Z, 224323/Z/21/Z) and Collaborative (200208/A/15/Z, 215599/Z/19/Z) Awards. MGN was supported by an ERC Advanced Grant (833247) and a Spinoza Grant of the Netherlands Organization for Scientific Research. The barcode sequencing performed by the Exeter Sequencing Facility utilised equipment funded by Wellcome (218247/Z/19/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.