Effect of progesterone onCandida albicansbiofilm formation under acidic conditions: a transcriptomic analysis

AbstractVulvovaginal candidiasis (VVC) caused byCandida albicansis a common disease worldwide. A very importantC. albicansvirulence factor is its ability to form biofilms on epithelium and/or on intrauterine devices promoting VVC. It has been shown that VVC has a hormonal dependency and that progesterone affects virulence traits ofC. albicanscells. To understand how the acidic environment (pH 4) and progesterone (either alone and in combination) modulateC. albicansresponse during formation of biofilm, a transcriptomic analysis was performed together with characterization of the biofilm properties. Compared to planktonic cells, acidic biofilm-cells exhibited major changes in their transcriptome, including modifications in the expression of 286 genes that were not previously associated with biofilm formation inC. albicans.The vast majority of the genes up-regulated in the acidic biofilm cells (including those uniquely identified here) are known targets of Sfl1, and the expression of this regulator impaired formation of the acidic biofilm. Under the acidic conditions used, progesterone treatment reducedC. albicansbiofilm biomass, structural cohesion, matrix quantity and susceptibility to fluconazole. Transcriptomic analysis of progesterone-exposed biofilms led to the identification of 65 down-regulated genes including, among others, the regulator Tec1 and several of its target genes suggesting that the function of this transcription factor is inhibited by the presence of the hormone. Overall, the results of this study show that progesterone modulatesC. albicansbiofilm formation and genomic expression under acidic conditions, which may have implications forC. albicanspathogenicity in the vaginal environment.Author summaryVulvovaginal candidiasis (VVC) is an infection of the vaginal tract that affects millions of women every year. It is caused by fungi of the genusCandida, mainlyCandida albicans.SeveralC. albicansvirulence factors contribute to the establishment of this infection, including the ability to form biofilms on vaginal walls and intrauterine devices.Candidaspecies belong to vaginal microflora, however under certain conditions they can cause infection. It has been shown that conditions that prompt VVC include those leading to high progesterone levels, as pregnancy. Here we show that progesterone impairs the ability ofC. albicanscells to form biofilms but causes a potential protective stress response. Indeed, we reveal an increased fluconazole resistance of biofilm cells grown in the presence of the hormone. Additionally, our results suggest that biofilm cells have a specific response to acidic conditions, as those established in the vaginal environment. Deepening the knowledge on the modulation ofC. albicansvirulence by vaginal conditions is essential for a full understanding of the pathogenesis of this species in the vaginal tract and contribute to the disclosure of new targets to treat VVC.