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

Abstract

The mechanisms by which <i>Candida glabrata</i> resists host defense peptides and caspofungin are incompletely understood. To identify transcriptional regulators that enable <i>C. glabrata</i> to withstand these classes of stressors, a library of 215 <i>C. glabrata</i> transcriptional regulatory deletion mutants was screened for susceptibility to both protamine and caspofungin. We identified eight mutants that had increased susceptibility to both host defense peptides and caspofungin. Of these mutants, six were deleted for genes that were predicted to specify proteins involved in histone modification. These genes were <i>ADA2</i>, <i>GCN5</i>, <i>SPT8</i>, <i>HOS2</i>, <i>RPD3</i>, and <i>SPP1</i> Deletion of <i>ADA2</i>, <i>GCN5</i>, and <i>RPD3</i> also increased susceptibility to mammalian host defense peptides. The Δ<i>ada2</i> and Δ<i>gcn5</i> mutants had increased susceptibility to other stressors, such as H₂O₂ and SDS. In the <i>Galleria mellonella</i> model of disseminated infection, the Δ<i>ada2</i> and Δ<i>gcn5</i> mutants had attenuated virulence, whereas in neutropenic mice, the virulence of the Δ<i>ada2</i> and Δ<i>rpd3</i> mutants was decreased. Thus, histone modification plays a central role in enabling <i>C. glabrata</i> to survive host defense peptides and caspofungin, and Ada2 and Rpd3 are essential for the maximal virulence of this organism during disseminated infection.