Epithelial cell death induced by Candidalysin, a cytolytic peptide toxin of Candida albicans

• Main Author: Blagojevic, Mariana
• Format: Dissertation
• Language: English
• Published: King's College London 2018

Microbial infections contribute significantly to morbidity and mortality in humans. Fungi are often an under-represented component of the microbial communities that colonise mucosal surfaces. The most common human fungal pathogens are the Candida species, of which Candida albicans is the most prevalent. C. albicans has an asymptomatic carriage rate of approximately 60% in the human population, where it resides as a member of the microflora that colonises the mucosal surfaces of the body. C. albicans is a polymorphic fungus capable of growing in a number of distinct morphological forms. At mucosal surfaces, growth of C. albicans in the unicellular yeast form is typically associated with commensalism, whereas the production of filamentous hyphae is associated with fungal overgrowth and pathogenesis. In healthy individuals, the immune system functions to restrict the growth of C. albicans hyphae, preventing infection. However, in the absence of effective immune surveillance, C. albicans hyphae can invade the mucosal surfaces of the body, causing infection and tissue damage. Translocation of C. albicans across mucosal barriers and invasion of underlying tissues is a major risk-factor for the development of life-threatening systemic infection in immune-compromised individuals. The hyphae of C. albicans secrete Candidalysin, a toxin essential for epithelial damage and activation of mucosal immune responses. Cellular damage sustained during infection can often result in cell death by apoptosis, necrosis, necroptosis or pyroptosis. While cell death is often regarded as being beneficial for microbial pathogenesis, it is becoming increasingly clear that cell death can also influence host defence by initiating specific immune responses that contribute to microbial clearance. Collectively, these data demonstrate that oral epithelial cells respond to the secreted fungal toxin Candidalysin by triggering numerous cellular stress responses that are intimately linked with the induction of cellular death. Candidalysin was observed to induce necrosis, but not apoptosis, necroptosis or pyroptosis, and promoted inflammatory responses through a mechanism involving necrosis-dependent release of pro-IL-1β and pro-IL-18.