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Bio-energetics Investigation of Candida albicans Using Real-time Extracellular Flux Analysis
Published on: March 19, 2019
Virulence of the fungal pathogen Candida albicans requires the five isoforms of protein mannosyltransferases
Mahmoud Rouabhia1, Martin Schaller, Cristina Corbucci
1Institut for Mikrobiologie, Universitätsstr. 1/26.12, 40225 Düsseldorf, Germany.
Abstract:
The PMT gene family in Candida albicans encodes five isoforms of protein mannosyltransferases (Pmt proteins Pmt1p, Pmt2p, Pmt4p, Pmt5p, and Pmt6p) that initiate O mannosylation of secretory proteins. We compared virulence characteristics of pmt mutants in two complex, three-dimensional models of localized candidiasis, using reconstituted human epithelium (RHE) and engineered human oral mucosa (EHOM); in addition, mutants were tested in a mouse model of hematogenously disseminated candidiasis (HDC). All pmt mutants showed attenuated virulence in the HDC model and at least one model of localized candidiasis. The pmt5 mutant, which lacks in vitro growth phenotypes, was less virulent in the EHOM and HDC assays but had no consistent phenotype in the RHE assay. In contrast, the pmt4 and pmt6 mutants were less virulent in the RHE and HDC assays but not in the EHOM assay. The results stress the contribution of all Pmt isoforms to the virulence of C. albicans and suggest that the importance of individual Pmt isoforms may differ in specific host niches. We propose that Pmt proteins may be suitable targets for future novel classes of antifungal agents.
Insights
All protein mannosyltransferase (Pmt) gene mutants in Candida albicans showed reduced virulence in mouse and human tissue models. Individual Pmt isoforms have varied importance in different host environments, suggesting potential antifungal targets.
Area of Science:
- Mycology
- Infectious Diseases
- Molecular Biology
Background:
- Candida albicans utilizes protein mannosyltransferases (Pmt) to initiate O-mannosylation of secretory proteins.
- The PMT gene family comprises five isoforms: Pmt1p, Pmt2p, Pmt4p, Pmt5p, and Pmt6p.
Purpose of the Study:
- To investigate the contribution of individual Pmt isoforms to Candida albicans virulence.
- To compare the virulence of pmt mutants in distinct in vitro and in vivo models of candidiasis.
Main Methods:
- Utilized reconstituted human epithelium (RHE) and engineered human oral mucosa (EHOM) as 3D models for localized candidiasis.
- Employed a mouse model of hematogenously disseminated candidiasis (HDC).
- Assessed virulence characteristics of various pmt mutants.
Main Results:
- All pmt mutants exhibited attenuated virulence in the HDC model and at least one localized candidiasis model.
- The pmt5 mutant showed reduced virulence in EHOM and HDC models but not RHE.
- The pmt4 and pmt6 mutants were less virulent in RHE and HDC models but not EHOM.
Conclusions:
- All Pmt isoforms contribute to Candida albicans virulence.
- The significance of individual Pmt isoforms varies across different host niches.
- Pmt proteins represent potential targets for novel antifungal agents.
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