A Host-Pathogen Interaction Screen Identifies ada2 as a Mediator of Candida glabrata Defenses Against Reactive Oxygen Species
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Abstract
Abstract Candida glabrata (C. glabrata) forms part of the normal human gut microbiota but can cause life-threatening invasive infections in immune-compromised individuals. C. glabrata displays high resistance to common azole antifungals, which necessitates new treatments. In this investigation, we identified five C. glabrata deletion mutants (∆ada2, ∆bas1, ∆hir3, ∆ino2 and ∆met31) from a library of 196 transcription factor mutants that were unable to grow and activate an immune response in Drosophila larvae. This highlighted the importance of these transcription factors in C. glabrata infectivity. Further ex vivo investigation into these mutants revealed the requirement of C. glabrata ADA2 for oxidative stress tolerance. We confirmed this observation in vivo whereby growth of the C. glabrata Δada2 strain was permitted only in flies with suppressed production of reactive oxygen species (ROS). Conversely, overexpression of ADA2 promoted C. glabrata replication in infected wild type larvae resulting in larval killing. We propose that ADA2 orchestrates the response of C. glabrata against ROS-mediated immune defenses during infection. With the need to find alternative antifungal treatment for C. glabrata infections, genes required for survival in the host environment, such as ADA2, provide promising potential targets.
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C. glabrata accounts for approximately 15-25% of invasive clinical cases.
“It accounts for approximately 15–25% of invasive clinical cases [8,11,12].”
From Candida glabrata: pathogenicity and resistance mechanisms for adaptation and survival (2021) · cites this paper as [8]
CgAda2 is essential for ROS survival in the Drosophila larvae model.
“Recently, Kounatidis et al. have identified the transcriptional adapter of the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex, CgAda2, by screening a library of 196 transcription factor mutants, to be essential for ROS survival in the Drosophila larvae model [88].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [88]
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References 62 · Cited by 13
- Authors
- Kounatidis, I., Ames, L., Mistry, R., Ho, H.-L., Haynes, K., & Ligoxygakis, P.
- Affiliations
- University of Oxford (GB)
- University of Exeter (GB)
- Corresponding author
- Ligoxygakis, Petros
- Venue
- G3 Genes Genomes Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-05-01
- Volume
- 8
- Issue
- 5
- Pages
- 1637-1647
- ISSN
- 2160-1836 (ISSN-L)
- PMC
- PMC5940155
- OpenAlex
- W2785998129
- Cited by
- 13
- References
- 62
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 2 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 1
- FWCI
- 0.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- G3 Genes Genomes Genetics (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Wellcome Trust
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/K500392/1)
- Bodossaki Foundation
- Biotechnology and Biological Sciences Research Council (BB/F005210/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Immunology and Microbiology › Immunology › Invertebrate Immune Response Mechanisms
- Keywords
- Candida glabrata, ADA2, host-pathogen interaction, reactive oxygen species, oxidative stress resistance, transcription factors, antifungal drug targets, BAS1, INO2, fungal virulence, azole resistance
- MeSH terms
- Animals, Candidiasis, Drosophila, Fungal Proteins, Larva, Phenotype, Transcription Factors, Gene Library, Gene Deletion, Reactive Oxygen Species, Candida glabrata, Gastrointestinal Tract, Host-Pathogen Interactions
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