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Cited by 250Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Infections and Studies

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Candida albicans-Epithelial Interactions: Dissecting the Roles of Active Penetration, Induced Endocytosis and Host Factors on the Infection Process

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Wächtler, Betty, Citiulo, Francesco, Jablonowski, Nadja, Förster, Stephanie, Dalle, Frederic, Schaller, Martin, Wilson, Duncan, Hube, Bernhard·2012·PLoS ONE
DOI 10.1371/journal.pone.0036952PMC PMC3351431
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Abstract

Candida albicans frequently causes superficial infections by invading and damaging epithelial cells, but may also cause systemic infections by penetrating through epithelial barriers. C. albicans is a remarkable pathogen because it can invade epithelial cells via two distinct mechanisms: induced endocytosis, analogous to facultative intracellular enteropathogenic bacteria, and active penetration, similar to plant pathogenic fungi. Here we investigated the contributions of the two invasion routes of C. albicans to epithelial invasion. Using selective cellular inhibition approaches and differential fluorescence microscopy, we demonstrate that induced endocytosis contributes considerably to the early time points of invasion, while active penetration represents the dominant epithelial invasion route. Although induced endocytosis depends mainly on Als3-E-cadherin interactions, we observed E-cadherin independent induced endocytosis. Finally, we provide evidence of a protective role for serum factors in oral infection: human serum strongly inhibited C. albicans adhesion to, invasion and damage of oral epithelial cells.

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Crossref · 10.1371/journal.pone.0036952

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Figures

Figure 1 Transmission electron microscopy of C. albicans epithelial invasion. Induced endocytosis of thimerosal killed hyphae (A), invasion of cytochalasin D treated epithelial cells by viable hyphae (B), invasion of untreated epithelial cells by viable hyphae (C), invasion of inactivated epithelial cells by viable hyphae (D).
Figure 1 Transmission electron microscopy of C. albicans epithelial invasion. Induced endocytosis of thimerosal killed hyphae (A), invasion of cytochalasin D treated epithelial cells by viable hyphae (B), invasion of untreated epithelial cells by viable hyphae (C), invasion of inactivated epithelial cells by viable hyphae (D).CC BY · PubMed Central
Figure 2 Contributions of fungal invasins, induced endocytosis and active penetration to C. albicans oral epithelial invasion. (A and B) Untreated or thimerosal-inactivated C. albicans cells were co-incubated with either untreated or cytochalasin D treated TR-146 oral epithelial cells for 2 h (A) and 3 h (B). After fixation, the samples were differentially stained and analyzed by fluorescence microscopy. The experiment was performed at least two times in duplicates. */**, indicates significant difference compared to the corresponding wild type control (Wt) (p<0.05/p<0.01, respectively). (C) Micrographs of invading hyphae. C. albicans appears blue (calcofluor white), with extracellular section of the hypha stained red (Concanavalin A); epithelial cells are stained yellow (Dil). Upper panel: a living hypha penetrating through several epithelial cells. Lower panel: a killed hypha, fully phagocytosed by an epithelial cell. Only viable hyphae are able to undergo inter-epithelial invasion. Numbers indicate the number of invaded epithelial cells and arrows mark internalized cells. Scale bar = 10 µm.
Figure 2 Contributions of fungal invasins, induced endocytosis and active penetration to C. albicans oral epithelial invasion. (A and B) Untreated or thimerosal-inactivated C. albicans cells were co-incubated with either untreated or cytochalasin D treated TR-146 oral epithelial cells for 2 h (A) and 3 h (B). After fixation, the samples were differentially stained and analyzed by fluorescence microscopy. The experiment was performed at least two times in duplicates. */**, indicates significant difference compared to the corresponding wild type control (Wt) (p<0.05/p<0.01, respectively). (C) Micrographs of invading hyphae. C. albicans appears blue (calcofluor white), with extracellular section of the hypha stained red (Concanavalin A); epithelial cells are stained yellow (Dil). Upper panel: a living hypha penetrating through several epithelial cells. Lower panel: a killed hypha, fully phagocytosed by an epithelial cell. Only viable hyphae are able to undergo inter-epithelial invasion. Numbers indicate the number of invaded epithelial cells and arrows mark internalized cells. Scale bar = 10 µm.CC BY · PubMed Central
Figure 3 Differential invasion of TR-146 or HeLa epithelial cells by C. albicans . (A) Oral TR-146 or HeLa epithelial cells were co-incubated with 105 C. albicans cells (alive or thimerosal killed – Wt+Thim) for either 1, 2 or 3 h. (B) HeLa epithelial cells were co-incubated with 105 indicated C. albicans strains (alive or thimerosal killed) for 3 h. Following fixation, samples were differentially stained and analyzed by fluorescence microscopy. The experiment was performed at least two times in duplicates. */**, indicates significant difference between cell lines (A) or between mutant and wild type (B) (p<0.05/p<0.01, respectively).
Figure 3 Differential invasion of TR-146 or HeLa epithelial cells by C. albicans . (A) Oral TR-146 or HeLa epithelial cells were co-incubated with 105 C. albicans cells (alive or thimerosal killed – Wt+Thim) for either 1, 2 or 3 h. (B) HeLa epithelial cells were co-incubated with 105 indicated C. albicans strains (alive or thimerosal killed) for 3 h. Following fixation, samples were differentially stained and analyzed by fluorescence microscopy. The experiment was performed at least two times in duplicates. */**, indicates significant difference between cell lines (A) or between mutant and wild type (B) (p<0.05/p<0.01, respectively).CC BY · PubMed Central
Figure 4 Adhesion, invasion and damage of oral epithelial cells by C. albicans in the presence of serum. (A) Adhesion of viable C. albicans cells to oral epithelial cells in cell culture medium supplemented with 10% human [hSerum] or fetal bovine serum [FBS]; (+) heat-treated; (−) untreated; ctr, C. albicans without serum. (B) Induced endocytosis of thimerosal-inactivated C. albicans hyphae. Either oral epithelial cells were supplemented with untreated and heat-treated 10% hSerum or FBS [EC] or C. albicans hyphae [Ca] were pre-incubated with untreated or heat-treated 40% serum; ctr killed hyphae without serum. (C) Cell damage of epithelial monolayers caused by viable C. albicans cells after 24 h in cell culture medium supplemented with untreated or heat-treated 10% hSerum or FBS compared to C. albicans infection with the addition of 1% serum (ctr). **, significant difference compared to control adhesion, invasion or damage (p≤0.01).
Figure 4 Adhesion, invasion and damage of oral epithelial cells by C. albicans in the presence of serum. (A) Adhesion of viable C. albicans cells to oral epithelial cells in cell culture medium supplemented with 10% human [hSerum] or fetal bovine serum [FBS]; (+) heat-treated; (−) untreated; ctr, C. albicans without serum. (B) Induced endocytosis of thimerosal-inactivated C. albicans hyphae. Either oral epithelial cells were supplemented with untreated and heat-treated 10% hSerum or FBS [EC] or C. albicans hyphae [Ca] were pre-incubated with untreated or heat-treated 40% serum; ctr killed hyphae without serum. (C) Cell damage of epithelial monolayers caused by viable C. albicans cells after 24 h in cell culture medium supplemented with untreated or heat-treated 10% hSerum or FBS compared to C. albicans infection with the addition of 1% serum (ctr). **, significant difference compared to control adhesion, invasion or damage (p≤0.01).CC BY · PubMed Central

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Metadata

Authors
Wächtler, B., Citiulo, F., Jablonowski, N., Förster, S., Dalle, F., Schaller, M., Wilson, D., & Hube, B.
Affiliations
  • Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE)
  • University of Tübingen (DE)
Corresponding author
Hube, Bernhard
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-05-14
Volume
7
Issue
5
Pages
e36952
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0036952
PMC
PMC3351431
OpenAlex
W1995203663
Cited by
250
References
45
Citations by year
2026: 11 · 2025: 19 · 2024: 19 · 2023: 29 · 2022: 23 · 2021: 25 · 2020: 21 · 2019: 15 · 2018: 19 · 2017: 17 · 2016: 12 · 2015: 11 · 2014: 15 · 2013: 10 · 2012: 4
FWCI
8.87
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
  • HAL (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Deutsche Forschungsgemeinschaft (Hu528/10, SPP1160)
  • Bundesministerium für Bildung und Forschung (0315901B)
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 › Infectious Diseases › Fungal Infections and Studies
Keywords
Candida albicans, epithelial invasion, ALS3, E-cadherin, oral epithelial cells, serum factors, fungal adhesion, host-pathogen interaction, oral candidiasis
MeSH terms
Blood Physiological Phenomena, Candida albicans, Candidiasis, Oral, Cell Adhesion, Cell Line, Endocytosis, Epithelial Cells, Fungal Proteins, Humans, Mouth Mucosa, Cadherins, Microscopy, Electron, Transmission, Host-Pathogen Interactions

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