Probing the role of histone acetylation in the evolution of pathogenicity in <i>Candida glabrata</i>

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 <i>C. glabrata</i> 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 <i>C. glabrata</i> 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 <i>C. glabrata </i>infection. Taken together these data suggest that genes associated with histone modifications, particularly histone acetylation/deacetylation pathways, have functionally diverged in the <i>C. glabrata</i> 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 <i>C. glabrata</i> infection, or to circumvent existing resistance to current antifungal therapies.<br>