Candidalysin biology and activation of host cells

Abstract

Candida albicans is an opportunistic fungal pathogen that can cause life-threatening systemic infections and distressing mucosal infections. A major breakthrough in understanding C. albicans pathogenicity was the discovery of candidalysin, the first cytolytic peptide toxin identified in a human pathogenic fungus. Secreted by C. albicans hyphae and encoded by the ECE1 gene, this 31-amino acid peptide integrates into and permeabilizes host cell membranes, causing damage across diverse cell types. Beyond its cytolytic activity, candidalysin can trigger potent innate immune responses in epithelial cells, macrophages, and neutrophils. Additionally, candidalysin plays a key role in nutrient acquisition during infection. This review explores the biology of candidalysin, its role in host cell activation, and extends the discussion to non-candidalysin Ece1p peptides, shedding light on their emerging significance.

Keywords: Candida albicans; candidalysin; fungal infection; immune mechanisms; toxins.

Fig 1

Candidalysin generation by C. albicans. The ECE1 gene is strongly expressed during C. albicans hyphal growth and encodes Ece1p, a polypeptide of 271 amino acids. The polypeptide is sequentially processed, first by Kex2p at lysine-arginine (KR) motifs (in red) to produce eight peptides, and then by Kex1p, which cleaves the terminal arginine residues. Candidalysin is the third peptide (position 62–92) and is 31 amino acids in length. SP = signal peptide. Created with BioRender.com.

Fig 2

Candidalysin activates epithelial cells. C. albicans hyphae are recognized by epithelial cells through the binding of host surface proteins, such as EGFR/HER2, to invasins and adhesins like Als3p, creating the invasion pocket (A). Candidalysin is secreted by hyphae and accumulates in the invasion pocket. It forms pores in the plasma membrane of epithelial cells, triggering calcium influx and LDH release. Candidalysin induces mitochondrial dysfunction by reducing intracellular ATP, reducing mitochondrial membrane potential (ΔΨm), increasing intracellular reactive oxygen species (ROS), and promoting the release of cytochrome c into the extracellular environment (B). Calcium influx stimulates the activation of matrix metalloproteinases, which release surface-tethered epidermal growth factor receptor (EGFR) ligands. These ligands bind to EGFR, triggering receptor dimerization and activation (C). EGFR activation stimulates ERK1/2, which activates the MAPK phosphatase MKP1. The transcription factor c-Fos is then activated, leading to the expression of cytokines (G-CSF, GM-CSF, IL-1α, and IL-1β), which are released from the cell and stimulate neutrophil recruitment and type 17 immunity at the site of infection. In parallel, candidalysin activates the p38-MAPK pathway, which can also activate EGFR and Hsp27 and stimulate IL-6 secretion (D). Created with BioRender.com.