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Fungal and Parasitic Infections

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

Elan E. Filler, Yaoping Liu, Norma V. Solis, Ling Wang, Luis F. Diaz, John E. Edwards Jr., Scott G. Filler, Michael R. Yeaman
Mairi C. Noverr, Editor
Elan E. Filler
aDivision of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, California, USA
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Yaoping Liu
aDivision of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, California, USA
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Norma V. Solis
aDivision of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, California, USA
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Ling Wang
bDivision of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, California, USA
cInstitute for Infection and Immunity, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
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Luis F. Diaz
bDivision of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, California, USA
cInstitute for Infection and Immunity, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
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John E. Edwards Jr.
aDivision of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, California, USA
cInstitute for Infection and Immunity, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
dDavid Geffen School of Medicine at UCLA, Los Angeles, California, USA
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Scott G. Filler
aDivision of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, California, USA
cInstitute for Infection and Immunity, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
dDavid Geffen School of Medicine at UCLA, Los Angeles, California, USA
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Michael R. Yeaman
bDivision of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, California, USA
cInstitute for Infection and Immunity, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
dDavid Geffen School of Medicine at UCLA, Los Angeles, California, USA
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Mairi C. Noverr
Tulane School of Medicine
Roles: Editor
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DOI: 10.1128/IAI.00146-20
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ABSTRACT

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 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 ADA2, GCN5, SPT8, HOS2, RPD3, and SPP1. Deletion of ADA2, GCN5, and RPD3 also increased susceptibility to mammalian host defense peptides. The Δada2 and Δgcn5 mutants had increased susceptibility to other stressors, such as H2O2 and SDS. In the Galleria mellonella model of disseminated infection, the Δada2 and Δgcn5 mutants had attenuated virulence, whereas in neutropenic mice, the virulence of the Δada2 and Δrpd3 mutants was decreased. Thus, histone modification plays a central role in enabling C. glabrata to survive host defense peptides and caspofungin, and Ada2 and Rpd3 are essential for the maximal virulence of this organism during disseminated infection.

FOOTNOTES

    • Received 9 March 2020.
    • Returned for modification 17 April 2020.
    • Accepted 4 December 2020.
    • Accepted manuscript posted online 14 December 2020.
  • Supplemental material is available online only.

  • Copyright © 2021 American Society for Microbiology.

All Rights Reserved.

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Identification of Candida glabrata Transcriptional Regulators That Govern Stress Resistance and Virulence
Elan E. Filler, Yaoping Liu, Norma V. Solis, Ling Wang, Luis F. Diaz, John E. Edwards Jr., Scott G. Filler, Michael R. Yeaman
Infection and Immunity Feb 2021, 89 (3) e00146-20; DOI: 10.1128/IAI.00146-20

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Identification of Candida glabrata Transcriptional Regulators That Govern Stress Resistance and Virulence
Elan E. Filler, Yaoping Liu, Norma V. Solis, Ling Wang, Luis F. Diaz, John E. Edwards Jr., Scott G. Filler, Michael R. Yeaman
Infection and Immunity Feb 2021, 89 (3) e00146-20; DOI: 10.1128/IAI.00146-20
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KEYWORDS

Candida glabrata
Antifungal Agents
histone modification
host defense peptide
virulence regulation

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