Candida albicans-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 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.

In vitro immune responses of human PBMCs against Candida albicans reveals fungal and leucocyte phenotypes associated with fungal persistence

“…During the host-C. albicans interaction, several parameters predispose to fungal disease, in particular C. albicans pathogenicity and host risk factors, such as immunosuppression (co-infections, immunosuppressive treatments and medical interventions) 4,[33][34][35] . However, these factors alone do not fully explain why, under comparable risk factor conditions, only some patients develop infections [7][8][9] .…”

Integrity under stress: Host membrane remodelling and damage by fungal pathogens

“…As the growing hyphae invade the cell, the PM will remodel to accommodate this invading protrusion. The mechanical forces exerted by the growing hypha are sufficient to penetrate the host cells even in the absence of secreted effectors (Allert et al, ). Curiously, this hyphae‐mediated penetration of the outer most epithelial barrier typically does not necessarily kill the host cell (Wachtler, Wilson, Haedicke, Dalle, & Hube, ).…”

“…For oral and vaginal epithelial cells, both wild‐type and ECE1 mutant strains invade and translocate. For intestinal epithelium, candidalysin secretion is required for full loss of epithelial integrity, cell damage, and epithelial translocation (Allert et al, ). The mechanism of membrane damage is still under investigation.…”

“Candida AlbicansInteractions With The Host: Crossing The Intestinal Epithelial Barrier”

“…In addition to evading AMPs, C. albicans has to cross the mucus layer to access and adhere to the layer of IECs. The mucins that mostly make up this protective layer modulate the morphology and physiology of C. albicans, 179 as exemplified by the mucin polymer Muc5AC expressed in the lung and the stomach that downregulate the expression of a range of genes related to adherence, filamentation and biofilm formation in C. albicans. 180 Moreover, the mucin Muc7 has been reported to exert a direct antimicrobial effect upon C. albicans in the oral cavity.…”