Sulfated glycosaminoglycans are host epithelial cell targets of the Candida albicans toxin candidalysin
Candidalysin, a cytolytic peptide produced by the fungal pathogen Candida albicans, is a key virulence factor. However, its host cell targets remain elusive. Here we performed a genome-wide loss-of-function CRISPR screen in the TR146 human oral epithelial cell line and identified that disruption of genes (XYLT2, B3GALT6 and B3GAT3) in glycosaminoglycan (GAG) biosynthesis conferred resistance to damage induced by candidalysin and live C. albicans. Surface plasmon resonance and atomic force and electron microscopy indicated that candidalysin binds to sulfated GAGs, facilitating its enrichment on the host cell surface. Adding exogenous sulfated GAGs or the analogue dextran sulfate protected cells against candidalysin-induced damage. Dextran sulfate also inhibited C. albicans invasion and fungal-induced epithelial cell cytokine production. In mice with vulvovaginal candidiasis, topical dextran sulfate administration reduced intravaginal tissue damage and inflammation. Collectively, sulfated GAGs are epithelial cell targets of candidalysin and can be used therapeutically to protect cells from candidalysin-induced damage.
Authors
- Robert J. Pyron (ORCID: https://orcid.org/0009-0009-1739-787X)
- Jianfeng Lin (ORCID: https://orcid.org/0000-0002-5202-6304)
- Gavin M. King (ORCID: https://orcid.org/0000-0002-5811-7012)
- Francisco N. Barrera (ORCID: https://orcid.org/0000-0002-5200-7891)
- Scott G. Filler (ORCID: https://orcid.org/0000-0001-7278-3700)
- Masato Tashiro (ORCID: https://orcid.org/0000-0001-7609-7679)
- Michael R. Yeaman (ORCID: https://orcid.org/0000-0002-9468-5252)
- Jian Miao (ORCID: https://orcid.org/0000-0001-7013-3800)
- Katherine G. Schaefer (ORCID: https://orcid.org/0000-0003-2180-799X)
- Jonathan S. Dordick (ORCID: https://orcid.org/0000-0001-7802-3702)
- Brian M. Peters (ORCID: https://orcid.org/0000-0002-0445-2077)
- Robert J. Linhardt
- Norma V. Solis (ORCID: https://orcid.org/0000-0001-5163-2110)
- Fuming Zhang (ORCID: https://orcid.org/0000-0003-2803-3704)
- C. Russell (ORCID: https://orcid.org/0000-0003-2489-657X)
- Hong Liu (ORCID: https://orcid.org/0000-0003-3491-3476)
- Quynh T. Phan
Institutions
- University of Tennessee Health Science Center (US)
- University of California, Los Angeles (US)
- Rensselaer Polytechnic Institute (US)
- UCLA Medical Center (US)
- Harbor–UCLA Medical Center (US)
- Nagasaki University (JP)
- University of Tennessee at Knoxville (US)
- University of Missouri (US)
Publication Details
- Journal
- Nature Microbiology
- Published
- 2024-09-16
- DOI
- https://doi.org/10.1038/s41564-024-01794-8
- Citations
- 17
- Primary Topic
- Antifungal resistance and susceptibility
- Type
- article
- Field-Weighted Citation Impact
- 6.61
Funders
- National Science Foundation
- University of Missouri
- China Scholarship Council
- Servier
- National Institutes of Health