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

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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 ada2 Δ and gcn5 Δ mutants also had increased susceptibility to other stressors such as H 2 O 2 and SDS. In the Galleria mellonella model of disseminated infection, the ada2 Δ and gcn5 Δ mutants had attenuated virulence, whereas in neutropenic mice, the virulence of the ada2 Δ and rpd3 Δ 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.

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