EGFR and HER2 receptor kinase signaling mediate epithelial cell invasion by Candida albicans during oropharyngeal infection
Open accessAbstract
The fungus Candida albicans is the major cause of oropharyngeal candidiasis (OPC). A key feature of this disease is fungal invasion of oral epithelial cells, a process that can occur by active penetration and fungal-induced endocytosis. Two invasins, Als3 and Ssa1, induce epithelial cell endocytosis of C. albicans , in part by binding to E-cadherin. However, inhibition of E-cadherin function only partially reduces C. albicans endocytosis, suggesting that there are additional epithelial cell receptors for this organism. Here, we show that the EGF receptor (EGFR) and HER2 function cooperatively to induce the endocytosis of C. albicans hyphae. EGFR and HER2 interact with C. albicans in an Als3- and Ssa1-dependent manner, and this interaction induces receptor autophosphorylation. Signaling through both EGFR and HER2 is required for maximal epithelial cell endocytosis of C. albicans in vitro. Importantly, oral infection with C. albicans stimulates the phosphorylation of EGFR and HER2 in the oral mucosa of mice, and treatment with a dual EGFR and HER2 kinase inhibitor significantly decreases this phosphorylation and reduces the severity of OPC. These results show the importance of EGFR and HER2 signaling in the pathogenesis of OPC and indicate the feasibility of treating candidal infections by targeting the host cell receptors with which the fungus interacts.
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C. albicans Als3 adhesin binds to epithelial cell receptors E-cadherin, EGFR, Her2, and c-Met, and to macrophage receptor CR3.
“the Als3 adhesin of C. albicans binds to receptors on epithelial cells, such as E-cadherin, EGFR, Her2, and c-Met, and receptors on macrophages, such as CR325–28.”
From Adhesin Als4112 promotes Candida auris skin colonization through interactions with keratinocytes and extracellular matrix proteins (2025) · cites this paper as [26]
A C. albicans als3Δ/Δ ssa1Δ/Δ mutant induces minimal phosphorylation of both EGFR and c-Met.
“Because Als3 and Ssa1 are surface expressed only on hyphae and are required for C. albicans to activate EGFR in oral epithelial cells [17], we tested a C. albicans als3Δ/Δ ssa1Δ/Δ mutant and found that it induced minimal phosphorylation of both EGFR and c-Met (Fig 5D–5F), suggesting that Als3 and/or Ssa1 are required for the activation of both receptors.”
From Candida albicans stimulates formation of a multi-receptor complex that mediates epithelial cell invasion during oropharyngeal infection (2023) · cites this paper as [17]
Als3 and/or Ssa1 are required for activation of both EGFR and c-Met.
“Because Als3 and Ssa1 are surface expressed only on hyphae and are required for C. albicans to activate EGFR in oral epithelial cells [17], we tested a C. albicans als3Δ/Δ ssa1Δ/Δ mutant and found that it induced minimal phosphorylation of both EGFR and c-Met (Fig 5D–5F), suggesting that Als3 and/or Ssa1 are required for the activation of both receptors.”
From Candida albicans stimulates formation of a multi-receptor complex that mediates epithelial cell invasion during oropharyngeal infection (2023) · cites this paper as [17]
Previously identified C. albicans invasins Als3 and Ssa1 mediate invasion of oral epithelial cells by interacting with E-cadherin and EGFR.
“Previously, we identified two C. albicans invasins, Als3 and Ssa1 that mediate invasion of oral epithelial cells by interacting with E-cadherin and EGFR [16,17,19].”
From Candida albicans stimulates formation of a multi-receptor complex that mediates epithelial cell invasion during oropharyngeal infection (2023) · cites this paper as [17]
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Self-citation
- Authors
- Zhu, W., Phan, Q. T., Boontheung, P., Solis, N. V., Loo, J. A., & Filler, S. G.
- Affiliations
- University of California, Los Angeles (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-08-13
- Volume
- 109
- Issue
- 35
- Pages
- 14194-14199
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3435201
- OpenAlex
- W2127891436
- Semantic Scholar
- b89c4da8fe464343e5c1294ab662acdee69463d1
- Cited by
- 180
- References
- 35
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 13 · 2023: 17 · 2022: 12 · 2021: 13 · 2020: 13 · 2019: 15 · 2018: 13 · 2017: 14 · 2016: 10 · 2015: 12 · 2014: 16 · 2013: 10 · 2012: 4
- FWCI
- 9.26
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR000124)
- Genentech
- National Institute of Dental and Craniofacial Research (R01DE013974, R01DE017088)
- National Center for Advancing Translational Sciences
- 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 albicans, oropharyngeal candidiasis, EGFR, HER2, receptor tyrosine kinase signaling, epithelial cell invasion, endocytosis, ALS3, Ssa1, E-cadherin, fungal virulence factors, dual kinase inhibitors, host-fungus interactions, oral mucosa
- MeSH terms
- Adenosine Triphosphatases, Animals, Candida albicans, Candidiasis, Oral, Disease Models, Animal, Endocytosis, Epithelial Cells, Fungal Proteins, Male, Mice, Inbred BALB C, Mouth Mucosa, Phosphorylation, Tyrosine, Signal Transduction, Cadherins, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, NIH 3T3 Cells, Mice, ErbB Receptors
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