Candidalysins: Mechanistic function of a novel family of fungal peptide toxins

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The mucosal (oral, vaginal, gastrointestinal) epithelium is of immense importance in protecting humans against a multitude of infections as it is the initial tissue encountered by the majority of microbes. Cytolytic proteins and peptide toxins are critical virulence factors of bacterial pathogens and play a major role in bacterial disease. Until very recently, human pathogenic fungi were not known to possess such toxins. The human fungal pathogen Candida albicans, the causative agent of thrush, causes millions of infections annually in people worldwide. An explanation for precisely how this fungus is able to cause mucosal disease has remained at the forefront of medical mycology and immunology for several decades. We have recently identified a secreted peptide toxin (Candidalysin) as an essential factor required for C. albicans infection at mucosal surfaces. This is the first cytolytic peptide toxin to be discovered in any human pathogenic fungus. Our work has shown that Candidalysin interacts with the membrane of epithelial cells, causing membrane damage, inflammation and destruction of host tissues. Production of this toxin by C. albicans is now understood to be a critically important step that facilitates mucosal infection and disease progression. Importantly, we have now identified similar Candidalysin toxins in the related fungal species C. dubliniensis and C. tropicalis, which are also pathogenic. Together with C. albicans, these fungi represent an immense health burden on the global population. The discovery of three Candidalysins identifies these toxins as a conserved family used by pathogenic Candida species to cause disease. Currently, there are no vaccines for Candida infections and the incidence of fungal pathogens acquiring resistance to commonly prescribed antifungal drugs is rising. Given their essential role in mucosal infection, understanding how this family of fungal toxins damage mucosal surfaces is critically important, and will pave the way towards therapeutic intervention that enables us to control and prevent disease progression. This proposal aims to identify exactly how Candidalysins interact with epithelial cell membranes to cause damage and infection. The findings of this work will be pivotal to our future understanding of fungal pathogenesis and will enable us to develop new strategies to engage with fungal infections to control their impact on the human population. This project will identify the Candidalysin family as new target, not only for the development of new antifungal drugs but also for the development of new vaccines, adjuvants, diagnostic tests and biomarkers for fungal infections.