Identification of Candida glabrata Transcriptional Regulators that Govern Stress Resistance and Virulence

The mechanisms by which Candida glabrata resists host defense peptides and caspofungin are incompletely understood. To identify transcriptional regulators that enable C. glabrata to withstand these classes of stressors, a library of 215 C. glabrata transcriptional regulatory deletion mutants was screened for susceptibility to both protamine and caspofungin. We identified 8 mutants that had increased susceptibility to both host defense peptides and caspofungin. Of these mutants, 6 were deleted for genes that were predicted to specify proteins involved in histone modification. These genes were ADA2, GCN5, SPT8, HOS2, RPD3, and SPP1. The ada2Δ and gcn5Δ mutants also had increased susceptibility to other stressors such as H2O2 and SDS. In the Galleria mellonella model of disseminated infection, the ada2Δ and gcn5Δ mutants had attenuated virulence, whereas in neutropenic mice, the virulence of the ada2Δ and rpd3Δ mutants was decreased. Thus, histone modification plays a central role in enabling C. glabrata to withstand host defense peptides and caspofungin, and Ada2 is essential for the maximal virulence of this organism during disseminated infection.