The Magnitude ofCandida albicansStress-Induced Genome Instability Results from an Interaction Between Ploidy and Antifungal Drugs

Abstract

Organismal ploidy and environmental stress impact the rates and types of mutational events. The opportunistic fungal pathogen Candida albicans, serves as a clinically relevant model for studying the interaction between eukaryotic ploidy and drug-induced mutagenesis. In this study, we compared the rates and types of genome perturbations in diploid and tetraploid C. albicans following exposure to two different classes of antifungal drugs; azoles and echinocandins. We measured mutations at three different scales: point mutation, loss-of-heterozygosity (LOH), and total DNA content for cells exposed to fluconazole and caspofungin. We found that caspofungin induced higher mutation rates than fluconazole, although this is likely an indirect consequence of stress-associated cell wall perturbations, rather than an inherent genotoxicity. Surprisingly, we found that antifungal drugs disproportionately elevated genome and ploidy instability in tetraploid C. albicans compared to diploids. Taken together, our results suggest that the magnitude of stress-induced mutagenesis results from an interaction between ploidy and antifungal drugs. These findings have both clinical and evolutionary implications for how fungal pathogens generate mutations in response to antifungal drug stress and how these mutations may facilitate the emergence of drug resistance.

Host association induces genome changes inCandida albicanswhich alters its virulence

“…The extreme genome instability observed in tetraploids, is partly due to intrinsic highly labile nature. It has been well established that tetraploid C. albicans has higher levels of genome instability compared to diploids (18,(22)(23)(24), and this phenomenon is also observed in related yeast species (44)(45)(46)(47). However, the impact of genetic background on tetraploid genome stability has been extremely limited to date (24).…”

“…As a highly heterozygous diploid (16), the C. albicans genome is highly labile and undergoes large-scale genome rearrangements like loss-of-heterozygosity (LOH) events and aneuploidy more frequently than small-scale DNA mutations. Furthermore, exposure to physiologically relevant stress conditions, including high temperature, oxidative stress, and antifungal drugs, increases LOH rates even further (17,18).…”

“…As a highly heterozygous diploid (16), the C. albicans genome is highly labile and undergoes large-scale genome rearrangements like loss-of-heterozygosity (LOH) events and aneuploidy more frequently than small-scale DNA mutations. Furthermore, exposure to physiologically relevant stress conditions, including high temperature, oxidative stress, and antifungal drugs, increases LOH rates even further (17,18).Another mechanism C. albicans uses to generate genetic variation is parasex, which involves diploid-diploid mating to produce tetraploids (19,20). Tetraploids undergo stochastic chromosome loss to return to diploid.…”

Chromatin Structure and Drug Resistance in Candida spp.

“…Interestingly, it has been shown in C. albicans that genome stability is altered by environmental triggers to promote the microevolution and adaptation of this species. For example, two recent studies found that C. albicans mutation rate is elevated during host infection [ 67 ], and in the presence of anti-fungal drugs [ 68 ] presumably to provide genetic raw material to the organism for survival under these stresses. Both studies also reveal the inconsistency of acquired genetic variation and how genome characteristics, such as differences in ploidy [ 68 ] and sub-telomeric chromatin structures [ 67 ], disproportionately elevate mutation mate.…”

“…For example, two recent studies found that C. albicans mutation rate is elevated during host infection [ 67 ], and in the presence of anti-fungal drugs [ 68 ] presumably to provide genetic raw material to the organism for survival under these stresses. Both studies also reveal the inconsistency of acquired genetic variation and how genome characteristics, such as differences in ploidy [ 68 ] and sub-telomeric chromatin structures [ 67 ], disproportionately elevate mutation mate. The mechanism by which such stress-induced mutagenesis arises remains to be determined, but taken together these findings suggest that regulators of genome architecture and chromatin structure may play a role in this process.…”