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RESEARCH ARTICLE
Keeping Candida commensal: how lactobacilli antagonize pathogenicity of Candida albicans in an in vitro gut model
Katja Graf, Antonia Last, Rena Gratz, Stefanie Allert, Susanne Linde, Martin Westermann, Marko Gröger, Alexander S. Mosig, Mark S. Gresnigt, Bernhard Hube
Disease Models & Mechanisms 2019 12: dmm039719 doi: 10.1242/dmm.039719 Published 12 September 2019
Katja Graf
1Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology–Hans-Knoell-Institute, Beutenbergstraße 11A, 07745 Jena, Germany
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Antonia Last
1Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology–Hans-Knoell-Institute, Beutenbergstraße 11A, 07745 Jena, Germany
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Rena Gratz
1Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology–Hans-Knoell-Institute, Beutenbergstraße 11A, 07745 Jena, Germany
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Stefanie Allert
1Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology–Hans-Knoell-Institute, Beutenbergstraße 11A, 07745 Jena, Germany
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Susanne Linde
2Center for Electron Microscopy Jena University Hospital, Ziegelmühlenweg 1, 07743 Jena, Germany
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Martin Westermann
2Center for Electron Microscopy Jena University Hospital, Ziegelmühlenweg 1, 07743 Jena, Germany
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Marko Gröger
3Center for Sepsis Control and Care (CSCC), University Hospital Jena, Am Klinikum 1, 07747 Jena, Germany
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Alexander S. Mosig
3Center for Sepsis Control and Care (CSCC), University Hospital Jena, Am Klinikum 1, 07747 Jena, Germany
4Institute of Biochemistry II, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany
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Mark S. Gresnigt
1Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology–Hans-Knoell-Institute, Beutenbergstraße 11A, 07745 Jena, Germany
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Bernhard Hube
1Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology–Hans-Knoell-Institute, Beutenbergstraße 11A, 07745 Jena, Germany
5Friedrich Schiller University, Fürstengraben 1, 07743 Jena, Germany
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  • For correspondence: bernhard.hube@hki-jena.de
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ABSTRACT

The intestine is the primary reservoir of Candida albicans that can cause systemic infections in immunocompromised patients. In this reservoir, the fungus exists as a harmless commensal. However, antibiotic treatment can disturb the bacterial microbiota, facilitating fungal overgrowth and favoring pathogenicity. The current in vitro gut models that are used to study the pathogenesis of C. albicans investigate the state in which C. albicans behaves as a pathogen rather than as a commensal. We present a novel in vitro gut model in which the fungal pathogenicity is reduced to a minimum by increasing the biological complexity. In this model, enterocytes represent the epithelial barrier and goblet cells limit C. albicans adhesion and invasion. Significant protection against C. albicans-induced necrotic damage was achieved by the introduction of a microbiota of antagonistic lactobacilli. We demonstrated a time-, dose- and species-dependent protective effect against C. albicans-induced cytotoxicity. This required bacterial growth, which relied on the presence of host cells, but was not dependent on the competition for adhesion sites. Lactobacillus rhamnosus reduced hyphal elongation, a key virulence attribute. Furthermore, bacterial-driven shedding of hyphae from the epithelial surface, associated with apoptotic epithelial cells, was identified as a main and novel mechanism of damage protection. However, host cell apoptosis was not the driving mechanism behind shedding. Collectively, we established an in vitro gut model that can be used to experimentally dissect commensal-like interactions of C. albicans with a bacterial microbiota and the host epithelial barrier. We also discovered fungal shedding as a novel mechanism by which bacteria contribute to the protection of epithelial surfaces.

This article has an associated First Person interview with the joint first authors of the paper.

Footnotes

  • Competing interests

    The authors declare no competing or financial interests.

  • Author contributions

    Conceptualization: K.G., A.L., B.H.; Methodology: K.G., A.L., R.G., S.A., S.L., M.W.; Software: S.L., M.W., M.S.G.; Validation: A.L.; Formal analysis: K.G., A.L., R.G., S.A., M.G., A.S.M., M.S.G.; Investigation: K.G., A.L., R.G.; Resources: B.H.; Writing - original draft: K.G., A.L.; Writing - review & editing: K.G., S.A., A.S.M., M.S.G., B.H.; Visualization: K.G., A.L.; Supervision: K.G., M.S.G., B.H.; Project administration: K.G., B.H.; Funding acquisition: B.H.

  • Funding

    B.H. and A.S.M. received funding from the European Union Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreements 812969 (FunHoMic) and 812954 (EUROoC). B.H., A.S.M. and A.L. were supported by the Center for Sepsis Control and Care (CSCC)/Bundesministerium für Bildung und Forschung (BMBF) (grant 01EO1002). A.L. is a member of the CSCC Research Training Group. B.H. and A.L. were further supported by the Infect ERA-NET Program (FunComPath; BMBF grant 031L0001A), and M.S.G. was supported by a Humboldt Research Fellowship (Alexander von Humboldt-Stiftung).

  • Supplementary information

    Supplementary information available online at http://dmm.biologists.org/lookup/doi/10.1242/dmm.039719.supplemental

  • Received March 20, 2019.
  • Accepted August 2, 2019.
  • © 2019. Published by The Company of Biologists Ltd
http://creativecommons.org/licenses/by/4.0

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Keywords

  • Candida albicans
  • Microbiota
  • Commensalism
  • Lactobacilli
  • Antagonism
  • In vitro model

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RESEARCH ARTICLE
Keeping Candida commensal: how lactobacilli antagonize pathogenicity of Candida albicans in an in vitro gut model
Katja Graf, Antonia Last, Rena Gratz, Stefanie Allert, Susanne Linde, Martin Westermann, Marko Gröger, Alexander S. Mosig, Mark S. Gresnigt, Bernhard Hube
Disease Models & Mechanisms 2019 12: dmm039719 doi: 10.1242/dmm.039719 Published 12 September 2019
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RESEARCH ARTICLE
Keeping Candida commensal: how lactobacilli antagonize pathogenicity of Candida albicans in an in vitro gut model
Katja Graf, Antonia Last, Rena Gratz, Stefanie Allert, Susanne Linde, Martin Westermann, Marko Gröger, Alexander S. Mosig, Mark S. Gresnigt, Bernhard Hube
Disease Models & Mechanisms 2019 12: dmm039719 doi: 10.1242/dmm.039719 Published 12 September 2019

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