Candidalysin triggers epithelial cellular stresses that induce necrotic death

Abstract

Candida albicans is a common opportunistic fungal pathogen that causes a wide range of infections from superficial mucosal to hematogenously disseminated candidiasis. The hyphal form plays an important role in the pathogenic process by invading epithelial cells and causing tissue damage. Notably, the secretion of the hyphal toxin candidalysin is essential for both epithelial cell damage and activation of mucosal immune responses. However, the mechanism of candidalysin‐induced cell death remains unclear. Here, we examined the induction of cell death by candidalysin in oral epithelial cells. Fluorescent imaging using healthy/apoptotic/necrotic cell markers revealed that candidalysin causes a rapid and marked increase in the population of necrotic rather than apoptotic cells in a concentration dependent manner. Activation of a necrosis‐like pathway was confirmed since C. albicans and candidalysin failed to activate caspase‐8 and ‐3, or the cleavage of poly (ADP‐ribose) polymerase. Furthermore, oral epithelial cells treated with candidalysin showed rapid production of reactive oxygen species, disruption of mitochondria activity and mitochondrial membrane potential, ATP depletion and cytochrome c release. Collectively, these data demonstrate that oral epithelial cells respond to the secreted fungal toxin candidalysin by triggering numerous cellular stress responses that induce necrotic death. Take aways Candidalysin secreted from Candida albicans causes epithelial cell stress. Candidalysin induces calcium influx and oxidative stress in host cells. Candidalysin induces mitochondrial dysfunction, ATP depletion and epithelial necrosis. The toxicity of candidalysin is mediated from the epithelial cell surface.

Calcium-dependent ESCRT recruitment and lysosome exocytosis maintain epithelial integrity during Candida albicans invasion

“…Therefore hyphal formation per se would be insufficient to cause damage. Only an increased burden of invasive hyphae, which deliver a critical level of candidalysin into the invasion pocket ( Mogavero et al., 2021 ), causes epithelial damage followed by necrotic cell death ( Ho et al., 2019 ; Blagojevic et al., 2021 ). Indeed, our work demonstrates that epithelial repair is an additional major player in this protective mechanism.…”

EGFR-MAPK adaptor proteins mediate the epithelial response to Candida albicans via the cytolytic peptide toxin, candidalysin

“…The discovery of the C. albicans -derived toxin, candidalysin, was a paradigm shift in understanding how hyphae promote pathogenesis, simultaneously causing target cell damage but also activating innate immune responses that are essential to limit control of this commensal microbe. This discovery led to a myriad of studies revealing how candidalysin activity interfaces with the host immune system and balances commensalism with pathogenicity (6–10, 13, 28–33)…”

Exploring the Inflammatory Pathogenesis of Colorectal Cancer

“…Acetaldehyde not only leads to DNA damage and oxidative stress, but also to tight junction disruption [ 143 ]. Candida albicans also secrete Candidalysin, a peptide toxin which leads to chromosomal translocation [ 144 ]. Mycotoxins, acetaldehyde and candidalysin are biochemical mediators that were recently identified to potentially play a role in colon carcinogenesis.…”

“…In addition to the aforementioned mechanisms by which fungi may contribute to the development of colon cancer, fungi also have a direct interaction with gut bacteria. Fungal–bacterial interactions have been shown to synergistically lead to pathogenesis, as well as cellular disruption [ 144 ]. Fungi directly aid in the formation of bacterial biofilms, leading to intestinal inflammation [ 122 , 145 ].…”