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Fungal septicemia is an increasingly common complication of immunocompromised patients worldwide. Candida species are the leading cause of invasive mycoses with  Candida glabrata  being the second most frequently isolated Candida species from Intensive Care Unit patients. Despite its clinical importance, very little is known about the mechanisms that  C. glabrata  employs to survive the antimicrobial and immune response of the mammalian host. Here, to decipher the interaction of  C. glabrata  with the host immune cells, we have screened a library of 18,350  C. glabrata  Tn 7  insertion mutants for reduced survival in human THP-1 macrophages  via  signature-tagged mutagenesis approach. A total of 56 genes, belonging to diverse biological processes including chromatin organization and golgi vesicle transport, were identified which are required for survival and/or replication of  C. glabrata  in macrophages. We report for the first time that  C. glabrata  wild-type cells respond to the intracellular milieu of macrophage by modifying their chromatin structure and chromatin resistance to micrococcal nuclease digestion, altered epigenetic signature, decreased protein acetylation and increased cellular lysine deacetylase activity are the hall-marks of macrophage-internalized  C. glabrata  cells. Consistent with this, mutants defective in chromatin organization  (Cgrsc3-aΔ ,  Cgrsc3-bΔ ,  Cgrsc3-aΔbΔ ,  Cgrtt109Δ ) and DNA damage repair ( Cgrtt107Δ ,  Cgsgs1Δ ) showed attenuated virulence in the murine model of disseminated candidiasis. Further, genome-wide transcriptional profiling analysis on THP-1 macrophage-internalized yeasts revealed deregulation of energy metabolism in  Cgrsc3-aΔ  and  Cgrtt109Δ  mutants. Collectively, our findings establish chromatin remodeling as a central regulator of survival strategies which facilitates a reprogramming of cellular energy metabolism in macrophage-internalized  C. glabrata  cells and provide protection against DNA damage.

Functional Genomic Analysis of Candida glabrata-Macrophage Interaction: Role of Chromatin Remodeling in Virulence