Histone deacetylase Sir2 promotes the systemic infection by facilitating its immune escape via remodeling the cell wall and maintaining the metabolic activity.

UNLABELLED

Histone deacetylation affects () pathogenicity by modulating virulence factor expression and DNA damage. The histone deacetylase Sir2 is associated with plasticity and maintains genome stability to help adapt to various environmental niches. However, whether Sir2-mediated chromatin modification affects virulence is unclear. The purpose of our study was to investigate the effect of Sir2 on pathogenicity and regulation. Here, we report that Sir2 is required for pathogenicity, as its deletion affects the survival rate, fungal burden in different organs and the extent of tissue damage in a mouse model of disseminated candidiasis. We evaluated the impact of Sir2 on virulence factors and revealed that the Sir2 null mutant had an impaired ability to adhere to host cells and was more easily recognized by the innate immune system. Comprehensive analysis revealed that the disruption of adhesion was due to a decrease in cell surface hydrophobicity rather than the differential expression of adhesion genes on the cell wall. In addition, Sir2 affects the distribution and exposure of mannan and β-glucan on the cell wall, indicating that Sir2 plays a role in preventing the immune system from recognizing . Interestingly, our results also indicated that Sir2 helps maintain metabolic activity under hypoxic conditions, suggesting that Sir2 contributes to colonization at hypoxic sites. In conclusion, our findings provide detailed insights into antifungal targets and a useful foundation for the development of antifungal drugs.

IMPORTANCE

() is the most common opportunistic fungal pathogen and can cause various superficial infections and even life-threatening systemic infections. To successfully propagate infection, this organism relies on the ability to express virulence-associated factors and escape host immunity. In this study, we demonstrated that the histone deacetylase Sir2 helps adhere to host cells and escape host immunity by mediating cell wall remodeling; as a result, successfully colonized and invaded the host . In addition, we found that Sir2 contributes to carbon utilization under hypoxic conditions, suggesting that Sir2 is important for survival and the establishment of infection in hypoxic environments. In summary, we investigated the role of Sir2 in regulating pathogenicity in detail; these findings provide a potential target for the development of antifungal drugs.