Candidalysin: discovery and function in Candida albicans infections

Abstract

Candidalysin is a cytolytic peptide toxin secreted by the invasive form of the human pathogenic fungus, Candida albicans. Candidalysin is critical for mucosal and systemic infections and is a key driver of host cell activation, neutrophil recruitment and Type 17 immunity. Candidalysin is regarded as the first true classical virulence factor of C. albicans but also triggers protective immune responses. This review will discuss how candidalysin was discovered, the mechanisms by which this peptide toxin contributes to C. albicans infections, and how its discovery has advanced our understanding of fungal pathogenesis and disease.

Figure 1

Candidalysin generation and activation of epithelial cells. C. albicans infections are initiated by increased fungal burdens with associated hypha formation. Hypha formation leads to the expression of ECE1, which encodes the Ece1p protein. Ece1p is processed by Kex2p after arginine residues at positions 61 and 93 (red arrows) to generate immature candidalysin (Clys). Immature candidalysin is further processed by Kex1p to remove the terminal Arg93 to generate mature candidalysin (SIIGIIMGILGNIPQVIQIIMSIVKAFKGNK: red α-helix) that is secreted from hyphae. (a) When accumulated at sufficient concentrations, candidalysin interacts with the cell membrane to form pore-like structures that results in membrane damage (LDH release) and calcium influx. (b) These events lead to the activation of matrix metalloproteinases and the release of epidermal growth factor receptor (EGFR) ligands, which ultimately leads to EGFR activation. (c) EGFR activation leads to induction of MAPK signalling (via p38, ERK1/2) and the activation of c-Fos. MKP1 activation (via ERK1/2) contributes to the regulation of the epithelial immune response (as it dephosphorylates p38). (d) c-Fos activation leads to chemokine and cytokine release and the subsequent recruitment of innate immune cells, including neutrophils and innate Type 17 cells (e.g. natural Th17 cells). Neutrophils phagocytose and kill the fungus and innate type 17 cells release IL-17 and IL-22. Together, these innate cells promote fungal clearance, activate epithelial tissues and improve barrier function, resulting in reduction in fungal burdens and/or clearance of the infection (commensalism).

Figure 2

Conceptual aspects of the dual function of candidalysin: virulence and avirulence. (a) In health, C. albicans acts as a commensal typified by asymptomatic carriage, producing low levels of candidalysin required for an efficient lifestyle. (b) Under conditions permitting C. albicans proliferation, increased candidalysin levels lead to damage of host cells and tissues (disease). (c) Concomitantly, increased candidalysin levels lead to the activation of protective innate responses via neutrophil recruitment and Type 17 immunity, resulting in fungal clearance. (d) In certain infections (i.e. vaginal) and when the immune response is dysregulated, increased candidalysin levels can lead to an overreaction of the immune response (immunopathology).