1.C.139.  The Candidalysin (CL) Family 

The Candida albicans virulence factor, candidalysin, polymerizes in solution to form membrane pores and damage epithelial cells (Russell et al. 2022).  C. albicans causes severe invasive candidiasis, and infection requires the virulence factor candidalysin (CL) which damages target cell membranes. CL forms membrane pores using a unique mechanism: it assembles into polymers in solution. The basic structural unit in polymer formation is a CL oligomer, which is sequentially added into a string configuration that can close into a loop. CL loops appear to spontaneously insert into the membrane to become pores. A CL mutation (G4W) inhibited the formation of polymers in solution and prevented pore formation in synthetic lipid systems. Epithelial cell studies showed that G4W CL failed to activate the danger response pathway, a hallmark of the pathogenic effect of CL. These results indicate that CL polymerization in solution is a necessary step for the damage of cellular membranes. Analysis of CL pores by atomic force microscopy revealed the co-existence of simple depressions and more complex pores, which are likely formed by CL assembled in an alternate oligomer orientation. This structural rearrangement represents a maturation mechanism that stabilizes pore formation to achieve more robust cellular damage. Thus, CL uses a previously unknown mechanism to damage membranes, whereby pre-assembly of CL loops in solution leads to formation of membrane pores. Thus, CL polymerization privides a novel therapeutic target to treat candidiasis (Russell et al. 2022).