| dc.description.abstract | Candida spp., especially Candida albicans, represent the third most frequent cause of infection in
Intensive Care Units worldwide, with a mortality rate approaching 40%. The increasing antifungal
resistance drastically reduces therapeutical options for treating candidiasis. Moreover, finding new
molecules that specifically recognize the microbial cell without damaging the host is further
complicated by the similarity between fungi and human cells.
Epigenetic writers and erasers have emerged as promising targets in different contexts, including
the treatment of fungal infections. In this context, histone acetylation-deacetylation plays a leading
role since it regulates pathogenic processes and influences C. albicans virulence, especially the Lys
56 of the H3 histone acetylation, particularly abundant in yeasts. The fungal sirtuin Hst3,
responsible for histone H3K56 deacetylation in C. albicans, is essential for the fungus viability and
virulence, representing a unique and interesting target for the development of new antifungals since
Hst family proteins diverge significantly from their human counterparts. In this study, using the
non-specific Hst3 inhibitor nicotinamide (NAM), the effects of H3K56ac accumulation in C.
albicans were evaluated. In particular, by Chromatin immunoprecipitation followed by sequencing
(ChIP-seq) analysis the acetylation patterns of H3K56 were identified in yeast promoting
conditions. In those conditions, Hst3 inhibition triggers the formation of a peculiar phenotype,
namely V-shaped hyphae, associated with increased levels of H3K56ac. Moreover, by RNA-seq
were identified some virulence-related genes regulated directly or indirectly by H3K56ac associated
to the promoter. Furthermore, the roles of H3K56ac in C. albicans infection were evaluated.
Specifically, since several studies pointed out the possible implication of C. albicans secretome in
mitigating innate immune cells response, the supernatants from Candida cultures, treated with
NAM (CaNAM-CM) or not (Ca-CM), were used to treat J774A.1 macrophages. Interestingly, the
exposure to the metabolites produced by NAM-treated C. albicans resulted in a rapid activation of
macrophages and an improved phagocytic activity. By contrast, the macrophages pre-stimulated
with Ca-CM displayed abnormal membrane ruffle and the phagocytosis resulted delayed.
Of note, quantitative MS analysis showed that farnesol, a quorum sensing molecule that also affects
innate immune system response, is significantly more abundant in CaNAM-CM. Finally, ChIP-seq
experiments in infection conditions revealed a different genomic distribution of H3K56ac. Also,
transcriptomic studies revealed a dysregulation of several genes associated to host immune evasion
and PAMPs exposure. Overall, this study provides the first map of H3K56 acetylation across the C.
albicans genome in two different growth conditions, representing a rich resource for future studies. [edited by Author] | it_IT |
