Characterizing the novel pore formation mechanism of the Candida albicans virulence factor candidalysin

Fungal infections infect millions of people per year. The most common cause is the normally commensal fungus Candida albicans. Typically a harmless member of our microbiome, C. albicans has the capacity to transition into a deadly pathogen, causing infections with mortality rates upwards of 50%. Though these infections have been studied for years and many virulence factors have been identified, a central cause eluded the field. A genetic screen identified the first ever human fungal pathogenic peptide, candidalysin, to be required for the inflammatory response and tissue damage hallmark of yeast infections, making it a therapeutic target to specifically target C. albicans infections. We successfully mapped and characterized the mechanism by which candidalysin forms membrane damaging pores in epithelial cell membranes to induce cellular toxicity. Candidalysin undergoes a novel mechanism of self-assembly in solution to form linear, flexible polymers. After achieving a specific length, these polymers close to form membrane-competent loops that bind and insert into target plasma membranes.