Gain-of-Function Mutations in PDR1 , a Regulator of Antifungal Drug Resistance in Candida glabrata, Control Adherence to Host Cells
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Candida glabrata is an emerging opportunistic pathogen that is known to develop resistance to azole drugs due to increased drug efflux. The mechanism consists of CgPDR1-mediated upregulation of ATP-binding cassette transporters. A range of gain-of-function (GOF) mutations in CgPDR1 have been found to lead not only to azole resistance but also to enhanced virulence. This implicates CgPDR1 in the regulation of the interaction of C. glabrata with the host. To identify specific CgPDR1-regulated steps of the host-pathogen interaction, we investigated in this work the interaction of selected CgPDR1 GOF mutants with murine bone marrow-derived macrophages and human acute monocytic leukemia cell line (THP-1)-derived macrophages, as well as different epithelial cell lines. GOF mutations in CgPDR1 did not influence survival and replication within macrophages following phagocytosis but led to decreased adherence to and uptake by macrophages. This may allow evasion from the host's innate cellular immune response. The interaction with epithelial cells revealed an opposite trend, suggesting that GOF mutations in CgPDR1 may favor epithelial colonization of the host by C. glabrata through increased adherence to epithelial cell layers. These data reveal that GOF mutations in CgPDR1 modulate the interaction with host cells in ways that may contribute to increased virulence.
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Candida glabrata azole resistance is coupled with selective fitness advantages in animal models of infection.
“We have shown in the past years that C. glabrata azole resistance is coupled with selective fitness advantages in animal models of infection (Ferrari et al. 2009; Vale-Silva et al. 2013).”
From Comparative Genomics of Two Sequential <i>Candida glabrata</i> Clinical Isolates (2017) · cites this paper as Vale-Silva et al. 2013
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- Authors
- Vale-Silva, L., Ischer, F., Leibundgut-Landmann, S., & Sanglard, D.
- Affiliations
- University of Lausanne (CH)
- Institute of Microbiology, Swiss Federal Institute of Technology, Zürich, Switzerland
- Venue
- Infection and Immunity
- Publisher
- American Society for Microbiology
- Published
- 2013-05
- Volume
- 81
- Issue
- 5
- Pages
- 1709-1720
- ISSN
- 0019-9567 (ISSN-L)
- 1098-5522
- PMC
- PMC3648025
- OpenAlex
- W2135694845
- Cited by
- 65
- References
- 44
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 2 · 2021: 9 · 2020: 4 · 2019: 5 · 2018: 8 · 2017: 5 · 2016: 7 · 2015: 4 · 2014: 3 · 2013: 3
- FWCI
- 4.13
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Infection and Immunity (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (123342)
- Medizinische Universität Wien
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- Candida glabrata, PDR1, gain-of-function mutations, antifungal resistance, azole resistance, drug efflux, ABC transporters, host-pathogen interaction, macrophage adhesion, epithelial cell adherence, virulence, innate immune evasion
- MeSH terms
- Animals, Bacterial Adhesion, Candidiasis, Disease Models, Animal, Female, Fungal Proteins, Macrophages, Mice, Inbred BALB C, Phagocytosis, Transcription Factors, Virulence, Gene Expression Regulation, Fungal, Cytokines, ATP-Binding Cassette Transporters, Drug Resistance, Fungal, Candida glabrata, Mice
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