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MBio. 2018 Jun 5;9(3). pii: e00915-18. doi: 10.1128/mBio.00915-18.

Candida albicans-Induced Epithelial Damage Mediates Translocation through Intestinal Barriers.

Author information

1
Department of Microbial Pathogenicity Mechanisms, Hans-Knöll-Institute, Jena, Germany.
2
Research Group Applied Systems Biology, Hans-Knöll-Institute, Jena, Germany.
3
Mucosal & Salivary Biology Division, Dental Institute, King's College London, London, United Kingdom.
4
Research Group Microbial Immunology, Hans-Knöll-Institute, Jena, Germany.
5
Aberdeen Fungal Group, MRC Centre for Medical Mycology, University of Aberdeen, Aberdeen, United Kingdom.
6
Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.
7
Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
8
Faculty of Biological Sciences, Friedrich-Schiller-University Jena, Jena, Germany.
9
Institute of Microbiology, Friedrich-Schiller-University Jena, Jena, Germany.
10
Department of Microbial Pathogenicity Mechanisms, Hans-Knöll-Institute, Jena, Germany bernhard.hube@leibniz-hki.de.
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Contributed equally

Abstract

Life-threatening systemic infections often occur due to the translocation of pathogens across the gut barrier and into the bloodstream. While the microbial and host mechanisms permitting bacterial gut translocation are well characterized, these mechanisms are still unclear for fungal pathogens such as Candida albicans, a leading cause of nosocomial fungal bloodstream infections. In this study, we dissected the cellular mechanisms of translocation of C. albicans across intestinal epithelia in vitro and identified fungal genes associated with this process. We show that fungal translocation is a dynamic process initiated by invasion and followed by cellular damage and loss of epithelial integrity. A screen of >2,000 C. albicans deletion mutants identified genes required for cellular damage of and translocation across enterocytes. Correlation analysis suggests that hypha formation, barrier damage above a minimum threshold level, and a decreased epithelial integrity are required for efficient fungal translocation. Translocation occurs predominantly via a transcellular route, which is associated with fungus-induced necrotic epithelial damage, but not apoptotic cell death. The cytolytic peptide toxin of C. albicans, candidalysin, was found to be essential for damage of enterocytes and was a key factor in subsequent fungal translocation, suggesting that transcellular translocation of C. albicans through intestinal layers is mediated by candidalysin. However, fungal invasion and low-level translocation can also occur via non-transcellular routes in a candidalysin-independent manner. This is the first study showing translocation of a human-pathogenic fungus across the intestinal barrier being mediated by a peptide toxin.IMPORTANCECandida albicans, usually a harmless fungus colonizing human mucosae, can cause lethal bloodstream infections when it manages to translocate across the intestinal epithelium. This can result from antibiotic treatment, immune dysfunction, or intestinal damage (e.g., during surgery). However, fungal processes may also contribute. In this study, we investigated the translocation process of C. albicans using in vitro cell culture models. Translocation occurs as a stepwise process starting with invasion, followed by epithelial damage and loss of epithelial integrity. The ability to secrete candidalysin, a peptide toxin deriving from the hyphal protein Ece1, is key: C. albicans hyphae, secreting candidalysin, take advantage of a necrotic weakened epithelium to translocate through the intestinal layer.

KEYWORDS:

Candida albicans; candidalysin; host cell damage; host cell invasion; intestinal barrier; necrosis; translocation

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