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

粘膜(口腔、阴道、胃肠道)上皮在保护人类免受多种感染方面具有极其重要的作用，因为它是大多数微生物遇到的初始组织。细胞溶解蛋白和多肽毒素是细菌病原体的关键毒力因子，在细菌疾病中起着重要作用。直到最近，人们还不知道人类致病真菌含有这种毒素。人类真菌病原体白色念珠菌是鹅口疮的病原体，每年在世界各地的人们中造成数百万人感染。几十年来，关于这种真菌如何能够导致粘膜疾病的确切解释一直处于医学真菌学和免疫学的前沿。我们最近发现一种分泌性多肽毒素(念珠菌素)是白念珠菌在粘膜表面感染所必需的一个重要因素。这是在人类致病真菌中发现的第一种溶细胞肽毒素。我们的工作表明，念珠菌素与上皮细胞的膜相互作用，引起膜的破坏，炎症和宿主组织的破坏。白念珠菌产生这种毒素现在被认为是促进粘膜感染和疾病进展的关键步骤。重要的是，我们现在已经在相关真菌物种都柏林假丝酵母和热带假丝酵母中发现了类似的念珠菌素毒素，这两种真菌也是致病的。与白色念珠菌一起，这些真菌给全球人口带来了巨大的健康负担。三种念珠菌毒素的发现将这些毒素确定为致病念珠菌物种用来致病的保守家族。目前，还没有针对念珠菌感染的疫苗，真菌病原体对常用抗真菌药物产生抗药性的发生率正在上升。鉴于它们在粘膜感染中的重要作用，了解这类真菌毒素如何损害粘膜表面至关重要，并将为我们能够控制和防止疾病进展的治疗干预铺平道路。这项建议旨在准确地确定念珠菌素是如何与上皮细胞膜相互作用而造成损害和感染的。这项工作的发现将是我们未来了解真菌发病机制的关键，并将使我们能够开发新的策略来参与真菌感染，以控制它们对人类群体的影响。该项目将确定念珠菌素家族为新的目标，不仅用于开发新的抗真菌药物，而且还用于开发用于真菌感染的新疫苗、佐剂、诊断测试和生物标记物。

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.