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

Histone deacetylation affectsCandida albicans (C. albicans) pathogenicity by modulating virulence factor expression and DNA damage. The histone deacetylase Sir2 is associated with C. albicans plasticity and maintains genome stability to help C. albicans adapt to various environmental niches. However, whether Sir2-mediated chromatin modificationaffectsC. albicans virulence is unclear. The purpose of our study was to investigate the effectof Sir2 on C. albicans pathogenicity and regulation. Here, we report that Sir2 is required for C. albicans pathogenicity, as its deletion affectsthe survival rate, fungal burden in differentorgans and the extent of tissue damage in a mouse model of disseminated candidiasis. We evaluated the impact of Sir2 on C. albicans 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 C. albicans adhesion was due to a decrease in cell surface hydrophobicity rather than the differentialexpression of adhesion genes on the cell wall. In addition, Sir2 affectsthe 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 C. albicans. Interestingly, our results also indicated that Sir2 helps C. albicans maintain metabolic activity under hypoxic conditions, suggesting that Sir2 contributes to C. albicans colonization at hypoxic sites. In conclusion, our findingsprovide detailed insights into antifungal targets and a useful foundation for the development of antifungal drugs.