<named-content content-type="genus-species">Candida albicans</named-content>-Induced Epithelial Damage Mediates Translocation through Intestinal Barriers

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 pathog...

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Autores principales:	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, Bernhard Hube
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Candida albicans candidalysin host cell damage host cell invasion intestinal barrier necrosis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8caa6f60252d4a35989645f46583594a
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spelling	oai:doaj.org-article:8caa6f60252d4a35989645f46583594a2021-11-15T16:00:26Z<named-content content-type="genus-species">Candida albicans</named-content>-Induced Epithelial Damage Mediates Translocation through Intestinal Barriers10.1128/mBio.00915-182150-7511https://doaj.org/article/8caa6f60252d4a35989645f46583594a2018-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00915-18https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE Candida 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.Stefanie AllertToni M. FörsterCarl-Magnus SvenssonJonathan P. RichardsonTony PawlikBetty HebeckerSven RudolphiMarc JuraschitzMartin SchallerMariana BlagojevicJoachim MorschhäuserMarc Thilo FiggeIlse D. JacobsenJulian R. NaglikLydia KasperSelene MogaveroBernhard HubeAmerican Society for MicrobiologyarticleCandida albicanscandidalysinhost cell damagehost cell invasionintestinal barriernecrosisMicrobiologyQR1-502ENmBio, Vol 9, Iss 3 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida albicans candidalysin host cell damage host cell invasion intestinal barrier necrosis Microbiology QR1-502
spellingShingle	Candida albicans candidalysin host cell damage host cell invasion intestinal barrier necrosis Microbiology QR1-502 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 Bernhard Hube <named-content content-type="genus-species">Candida albicans</named-content>-Induced Epithelial Damage Mediates Translocation through Intestinal Barriers
description	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. IMPORTANCE Candida 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.
format	article
author	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 Bernhard Hube
author_facet	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 Bernhard Hube
author_sort	Stefanie Allert
title	<named-content content-type="genus-species">Candida albicans</named-content>-Induced Epithelial Damage Mediates Translocation through Intestinal Barriers
title_short	<named-content content-type="genus-species">Candida albicans</named-content>-Induced Epithelial Damage Mediates Translocation through Intestinal Barriers
title_full	<named-content content-type="genus-species">Candida albicans</named-content>-Induced Epithelial Damage Mediates Translocation through Intestinal Barriers
title_fullStr	<named-content content-type="genus-species">Candida albicans</named-content>-Induced Epithelial Damage Mediates Translocation through Intestinal Barriers
title_full_unstemmed	<named-content content-type="genus-species">Candida albicans</named-content>-Induced Epithelial Damage Mediates Translocation through Intestinal Barriers
title_sort	<named-content content-type="genus-species">candida albicans</named-content>-induced epithelial damage mediates translocation through intestinal barriers
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/8caa6f60252d4a35989645f46583594a
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<named-content content-type="genus-species">Candida albicans</named-content>-Induced Epithelial Damage Mediates Translocation through Intestinal Barriers

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