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

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

doi:10.1128/mbio.00915-18

Abstract

ABSTRACTLife-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.

Highlights

Life-threatening systemic infections often occur due to the translocation of pathogens across the gut barrier and into the bloodstream
We hypothesized that this particular type of translocation from the gut into the bloodstream requires invasion into intestinal epithelial cells (IECs) that is associated with fungus-induced cellular damage and loss of epithelial barrier integrity
Since in vitro translocation of C. albicans correlated with cytotoxicity, we investigated whether C. albicans factors necessary for damage of IECs might play a role in fungal translocation

Summary

Introduction

Life-threatening systemic infections often occur due to the translocation of pathogens across the gut barrier and into the bloodstream. Fungal invasion and low-level translocation can 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). A balanced and diverse microbiota [14], the secretion of antimicrobial peptides (AMPs) [15], and the concerted activity of the innate and adaptive immune systems [14, 16] act to reduce hyphal burdens during periods of fungal overgrowth and restrict the fungus to the commensal (yeast) morphology Dysfunctions in these protective mechanisms can favor C. albicans translocation. Disseminated candidiasis is typically a nosocomial infection, and intensive care unit (ICU) patients are susceptible to invasive C. albicans infections [19,20,21]

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Conclusion