AbstractWith the advancement of modern medicine, invasive fungal infections are a growing cause of global mortality. Candida glabrata accounts for 25% of fungal infections in UK hospitals, second only to C. albicans. This number is expected to rise given current treatment challenges due to the former’s intrinsic antifungal resistance. C. glabrata also possesses a particularly interesting phylogeny, being a pathogen that is closely related to the non-pathogenic yeast S. cerevisiae. This makes C. glabrata a valuable model species to investigate evolutionary adaptation at a molecular level. Comparative genomics suggests that histone modification-related genes are under positive selection in this species, and polymorphisms in these genes have influenced the adaptation of this species to the human host environment.
Analyses conducted in this project suggest that histone acetylation pathways are not only under positive selection, but contribute to pathogenic phenotypes in C. glabrata. It was shown that the deletion of genes involved in histone acetylation produced hypervirulent C. glabrata strains, as determined by in vitro and in vivo phenotyping assays. Strains individually lacking subunits of histone acetyltransferase complexes showed increase azole resistance, variance in stress responses, increased biofilm formation and greater virulence in an insect infection model. These strains also showed substantially different transcriptomic profiles to the wild-type yeast and in context with the literature, transcriptomic data suggests that these histone acetylation-related genes have functionally diverged in the C. glabrata lineage, in accordance with our in silico predictions. It was therefore hypothesised that interfering with histone acetylation levels, by using histone deacetylase inhibitors, would attenuate the virulence of this fungal pathogen. Treating C. glabrata with histone deacetylase inhibitors attenuated biofilm formation and azole resistance and RNA-seq analyses indicated that the inhibition of deacetylation pathways altered the yeast’s transcriptional response to antifungal treatment. An in vivo insect infection model also suggested that histone deacetylase inhibitor treatment, in combination with the established antifungal fluconazole, could increase the survival rate of individuals suffering from C. glabrata infection. Taken together these data suggest that genes associated with histone modifications, particularly histone acetylation/deacetylation pathways, have functionally diverged in the C. glabrata lineage, to promote virulence-associated phenotypes. By extension genetic polymorphisms in components of these pathways may have influenced the species emergence as a human pathogen. Such processes may be pharmacologically targeted as an alternative means of treating C. glabrata infection, or to circumvent existing resistance to current antifungal therapies.
|Date of Award||Jul 2020|
|Supervisor||Edel Hyland (Supervisor) & John McGrath (Supervisor)|
- Candida glabrata
- Antifungal resistance