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Candida albicans-induced epithelial damage mediates translocation through intestinal barriers

Autoren: Stefanie Allert & Toni M. Förster, Carl-Magnus Svensson, Jonathan P. Richardson, Tony Pawlik, Betty Hebecker, Sven Rudolphi, Marc Juraschitz, Martin Schaller, Mariana Blagojevic, Joachim Morschhäuser, Marc Thilo Figge, Ilse D. Jacobsen, Julian R. Naglik, Lydia Kasper, Selene Mogavero and Bernhard Hube

Vollständiger Artikel: https://www.ncbi.nlm.nih.gov/pubmed/?term=29871918externer Link

Foto: Erstautoren Stefanie Allert & Toni M. Förster

Stefanie Allert & Toni Förster

Kommentar: Candida albicans ist normalerweise ein harmloser Besiedler von Schleimhäuten des Menschen, kann aber nach Translokation in das Blutgefäßsystem lebensbedrohliche systemische Infektionen hervorrufen. Diese Publikation beschreibt die erste detaillierte Studie über die Translokation des humanpathogenen Pilzes Candida albicans durch intestinale Epithelbarrieren. Sie zeigt, dass die Translokation mit Hyphenbildung und nekrotischen Zellschädigungen assoziiert ist und von der Sekretion des erst kürzlich entdeckten Peptidtoxin Candidalysin abhängt.

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 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 > 2000 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 fungal-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 Candidalysin-mediated. 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.

Letztauthor/Corresponding author:

Bernhard Hube
Department of Microbial Pathogenicity Mechanisms,
Leibniz Institute for Natural Product Research and Infection Biology –
Hans Knoell Institute Jena (HKI) Beutenbergstraße 11a
D-07745 Jena, Germany
bernhard.hube@leibniz-hki.de
Tel:+ 49(0)3641 532 1401

Kontaktadresse der Erstautoren (shared first author):
Stefanie Allert, Toni Förster
Department of Microbial Pathogenicity Mechanisms,
Leibniz Institute for Natural Product Research and Infection Biology –
Hans Knoell Institute Jena (HKI) Beutenbergstraße 11a
D-07745 Jena, Germany
stefanie.allert@leibniz-hki.de
toni.foerster@leibniz-hki.de
Tel: +49(0)3641-5321141 oder 1390