| Popis: |
Candidiasis is one of the most prevalent mycoses worldwide, and there are few successful treatments for this disease. In the UK, Candida glabrataaccounts for 25 % of Candida infections, and due to the increasing incidence of multidrug resistance, C. glabrata poses an eminent threat to public health, exacerbated by the limited range of antifungal therapies. Our aim is to elucidate the molecular mechanisms underlying the emergence of pathogenicity in the C. glabrata lineage, to identify novel therapeutical targets. Using comparative phylogenomics, we putatively identified 19 genes under positive selection in the C. glabrata lineage. Each of these genes influences chromatin structure by regulating histone post-translational modifications (PTMs). To assess the contribution of these genes to virulence, we monitored the phenotypic consequences of individually removing each gene in clinically-relevant assays. To date, we have focused on 3 genes, cg-SPP1 (regulates histone H3 methylation), cg-HAT1 (histone H4 acetyltransferase) and cg-AHC1 (subunit of Ada histone acetyltransferase complex). Preliminary data show that the individual deletion of these genes increases biofilm formation and fluconazole resistance in C. glabrata. Furthermore, acetyltransferase knockout strains show hypervirulence in an in vivo Galleria melonella infection model, and phenotypic differences in abiotic stress assays. RNA-sequencing was performed on the type-strain, cg-hat1Δ, and cg-ahc1Δ, in the presence and absence of fluconazole to determine the molecular bases for these phenotypes, revealing commonality between differentially expressed genes in both mutants. Together, our data suggest that histone PTMs play a significant, and overlapping, role in dictating virulence in C. glabrata, and detail the global transcriptomic response to fluconazole. |
