Publicação
Candida species vaginal virulence determinants: role of environmental factors
| Resumo: | Candida species are relevant opportunistic fungi in the vaginal tract, where they may transform a symptomless colonization into an infection, vulvovaginal candidiasis (VVC). The high incidence of VVC, its negative consequences and the increase of antifungal failure in its treatment, make it crucial to increase the knowledge on vaginal virulence of the most common Candida species in VVC, Candida albicans and Candida glabrata. Thus, this investigation aimed to analyse the modulation of relevant Candida virulence factors by specific vaginal conditions, as the acidic environment and presence of hormones, as well as the identification of potential vaginal virulence determinants. The first step of this work was the analysis of pH influence on the biofilm development of C. albicans and C. glabrata vaginal isolates. The pH was found to affect biofilms’ biomass, structure and matrix composition of both species, being C. glabrata biofilm formation favored at acidic conditions and in C. albicans at neutral pH. Candida glabrata acidic biofilms were further analysed, focusing on matrix production, which was verified to be negatively regulated by the Zap1 transcription factor. Zap1 blocked the secretion of 31 proteins, some with a potential role on carbohydrate matrix delivery. Zap1 was also found to induce the secretion of 134 proteins, revealing a potential role on the modulation of C. glabrata matrix proteomic profile by acidic conditions, reporting 397 proteins, for the first time, in the matrix. The influence of reproductive hormones, progesterone and β-estradiol, on C. albicans and C. glabrata vaginal isolates at acidic conditions was also evaluated. The hormones led to a dose-dependent increase of cells’ resistance to hydrogen peroxide and azoles, in both species, and were also found to affect C. albicans biofilm formation and filamentation but not C. glabrata biofilm development. Consistently, a transcriptomic analysis of C. albicans biofilms developed in the presence of progesterone led to the identification of 166 repressed genes including, among others, the regulator Tec1 and many of its target genes, and also 54 up-regulated genes, including the efflux pumps Cdr1 and Cdr2. The transcriptomic profile of C. albicans acidic biofilms was also analysed in the absence of hormone, being revealed 286 genes not previously associated with biofilm formation in C. albicans, many regulated by Sfl1, which was found to be essential for biofilm formation at acidic conditions. Overall this study shows that vaginal conditions have a species-specific modulation of Candida virulence factors, being revealed new putative vaginal virulence determinants, thus contributing to a better knowledge of Candida vaginal pathogenicity. |
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| Autores principais: | Gonçalves, Bruna Fernandes |
| Assunto: | Candida species vaginal environment virulence determinants vulvovaginal candidiasis candidíase vulvovaginal determinantes de virulência vaginal espécies de Candida |
| Ano: | 2019 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | português |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | Candida species are relevant opportunistic fungi in the vaginal tract, where they may transform a symptomless colonization into an infection, vulvovaginal candidiasis (VVC). The high incidence of VVC, its negative consequences and the increase of antifungal failure in its treatment, make it crucial to increase the knowledge on vaginal virulence of the most common Candida species in VVC, Candida albicans and Candida glabrata. Thus, this investigation aimed to analyse the modulation of relevant Candida virulence factors by specific vaginal conditions, as the acidic environment and presence of hormones, as well as the identification of potential vaginal virulence determinants. The first step of this work was the analysis of pH influence on the biofilm development of C. albicans and C. glabrata vaginal isolates. The pH was found to affect biofilms’ biomass, structure and matrix composition of both species, being C. glabrata biofilm formation favored at acidic conditions and in C. albicans at neutral pH. Candida glabrata acidic biofilms were further analysed, focusing on matrix production, which was verified to be negatively regulated by the Zap1 transcription factor. Zap1 blocked the secretion of 31 proteins, some with a potential role on carbohydrate matrix delivery. Zap1 was also found to induce the secretion of 134 proteins, revealing a potential role on the modulation of C. glabrata matrix proteomic profile by acidic conditions, reporting 397 proteins, for the first time, in the matrix. The influence of reproductive hormones, progesterone and β-estradiol, on C. albicans and C. glabrata vaginal isolates at acidic conditions was also evaluated. The hormones led to a dose-dependent increase of cells’ resistance to hydrogen peroxide and azoles, in both species, and were also found to affect C. albicans biofilm formation and filamentation but not C. glabrata biofilm development. Consistently, a transcriptomic analysis of C. albicans biofilms developed in the presence of progesterone led to the identification of 166 repressed genes including, among others, the regulator Tec1 and many of its target genes, and also 54 up-regulated genes, including the efflux pumps Cdr1 and Cdr2. The transcriptomic profile of C. albicans acidic biofilms was also analysed in the absence of hormone, being revealed 286 genes not previously associated with biofilm formation in C. albicans, many regulated by Sfl1, which was found to be essential for biofilm formation at acidic conditions. Overall this study shows that vaginal conditions have a species-specific modulation of Candida virulence factors, being revealed new putative vaginal virulence determinants, thus contributing to a better knowledge of Candida vaginal pathogenicity. |
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