Effect of progesterone on Candida albicans biofilm formation under acidic conditions: a transcriptomic analysis

Abstract Vulvovaginal candidiasis (VVC) caused by Candida albicans is a common disease worldwide. A very important C. albicans virulence 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 of C. albicans cells. To understand how the acidic environment (pH 4) and progesterone (either alone and in combination) modulate C. albicans response 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 in C. 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 reduced C. albicans biofilm 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 modulates C. albicans biofilm formation and genomic expression under acidic conditions, which may have implications for C. albicans pathogenicity in the vaginal environment. Author summary Vulvovaginal candidiasis (VVC) is an infection of the vaginal tract that affects millions of women every year. It is caused by fungi of the genus Candida , mainly Candida albicans. Several C. albicans virulence factors contribute to the establishment of this infection, including the ability to form biofilms on vaginal walls and intrauterine devices. Candida species 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 of C. albicans cells 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 of C. albicans virulence 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.