Mechanisms of Candida albicans commensalism and pathogenicity

Fungal pathogens kill ~2.5 million people every year, six times more than malaria or influenza, and are deadlier than most bacterial infections. In direct response to these alarming figures, the World Health Organisation recently commissioned the first ‘fungal priority pathogens’ list, and cited Candida albicans in the ‘critical’ group (of highest concern). This response highlights the need to better understand the biological processes that drive and influence C. albicans pathogenesis.
During infection, C. albicans can alter its morphology from yeast cells to invasive ‘pathogenic’ hyphae. However, the transition from yeast to hyphae is a tightly regulated process, and subject to environmental and genetic influences. Critically, clinical isolates of C. albicans often display a “spectrum of pathogenicity”, ranging from overtly pathogenic (producing invasive hyphae, invading tissues, and causing damage), to overtly commensal (producing no invasive hyphae and causing no tissue damage). These observations suggest that an additional level of regulation influences C. albicans pathogenicity.
C. albicans hyphae are ‘pathogenic’ at mucosal surfaces because they secrete candidalysin; a pore-forming peptide toxin that causes tissue damage, inflammation, and symptomology. To produce candidalysin, C. albicans must express a gene called ECE1. Once expressed, the Ece1 protein is processed into eight small peptides, the third of which is candidalysin. Importantly, efficient processing of Ece1 is context-dependent, and essential for candidalysin production, while the amino acid sequence of candidalysin is also critical for toxicity and potency. However, while candidalysin secretion is critical for pathogenicity, it is only the final step in a carefully regulated cascade of events that are required for full C. albicans virulence, including adhesion; invasion; hyphal maintenance; ECE1 expression, and candidalysin processing and secretion.
Numerous studies have catalogued the fungal...