TY  - JOUR
A1  - Allert, Stefanie
A1  - Förster, Toni M.
A1  - Svensson, Carl-Magnus
A1  - Richardson, Jonathan P.
A1  - Pawlik, Tony
A1  - Hebecker, Betty
A1  - Rudolphi, Sven
A1  - Juraschitz, Marc
A1  - Schaller, Martin
A1  - Blagojevic, Mariana
A1  - Morschhäuser, Joachim
A1  - Figge, Marc Thilo
A1  - Jacobsen, Ilse D.
A1  - Naglik, Julian R.
A1  - Kasper, Lydia
A1  - Mogavero, Selene
A1  - Hube, Bernhard
T1  - \(Candida\) \(albicans\)-Induced Epithelial Damage Mediates Translocation through Intestinal Barriers
T2  - mBio
N2  - 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.
KW  - Candida albicans
KW  - candidalysin
KW  - host cell damage
KW  - host cell invasion
KW  - intestinal barrier
KW  - necrosis
KW  - translocation
Y1  - 2018
UR  - https://opus.bibliothek.uni-wuerzburg.de/opus4-wuerzburg/frontdoor/index/index/docId/22108
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-221084
VL  - 9
IS  - 3
ER  -