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- Title
Glucose-enhanced oxidative stress resistance—A protective anticipatory response that enhances the fitness of Candida albicans during systemic infection.
- Authors
Larcombe, Daniel E.; Bohovych, Iryna M.; Pradhan, Arnab; Ma, Qinxi; Hickey, Emer; Leaves, Ian; Cameron, Gary; Avelar, Gabriela M.; de Assis, Leandro J.; Childers, Delma S.; Bain, Judith M.; Lagree, Katherine; Mitchell, Aaron P.; Netea, Mihai G.; Erwig, Lars P.; Gow, Neil A. R.; Brown, Alistair J. P.
- 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. Author summary: In response to certain host signals, the major fungal pathogen Candida albicans activates anticipatory responses that protect it against impending attack by innate immune cells. These responses include immune evasion via the masking or shaving of pathogen-associated molecular patterns in response to lactate, hypoxia, iron depletion or neutral pH. These responses also include glucose-induced resistance to acute oxidative stress, which protects the fungus against killing by innate immune cells. In this study we define key signalling and cellular mechanisms that underlie "glucose-enhanced oxidative stress resistance". This phenotype is regulated by the glucose repression and cyclic AMP-protein kinase A signalling pathways, and is dependent on the accumulation of the known stress-protectant, trehalose, in response to glucose. Glucose-enhanced oxidative stress resistance is not observed in environmental yeasts or in other pathogenic Candida species, including Candida dubliniensis, a close cousin of C. albicans. This reinforces the view that, due to the additional fitness costs they impose, the anticipatory responses displayed by a microbe reflect the environmental pressures it has recently faced in the niches in which it has evolved.
- Subjects
CANDIDA albicans; OXIDATIVE stress; ECHINOCANDINS; TREHALOSE; EXPECTATION (Psychology); KLUYVEROMYCES marxianus; BINDING site assay; CELLULAR signal transduction
- Publication
PLoS Pathogens, 2023, Vol 19, Issue 7, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1011505