Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, Beutenbergstrasse 11a, Jena, 07745, Germany.
Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, München, 81675, Germany.
Nat Commun. 2018 Oct 15;9(1):4260. doi: 10.1038/s41467-018-06607-1.
Clearance of invading microbes requires phagocytes of the innate immune system. However, successful pathogens have evolved sophisticated strategies to evade immune killing. The opportunistic human fungal pathogen Candida albicans is efficiently phagocytosed by macrophages, but causes inflammasome activation, host cytolysis, and escapes after hypha formation. Previous studies suggest that macrophage lysis by C. albicans results from early inflammasome-dependent cell death (pyroptosis), late damage due to glucose depletion and membrane piercing by growing hyphae. Here we show that Candidalysin, a cytolytic peptide toxin encoded by the hypha-associated gene ECE1, is both a central trigger for NLRP3 inflammasome-dependent caspase-1 activation via potassium efflux and a key driver of inflammasome-independent cytolysis of macrophages and dendritic cells upon infection with C. albicans. This suggests that Candidalysin-induced cell damage is a third mechanism of C. albicans-mediated mononuclear phagocyte cell death in addition to damage caused by pyroptosis and the growth of glucose-consuming hyphae.
清除入侵的微生物需要先天免疫系统的吞噬细胞。然而，成功的病原体已经进化出复杂的策略来逃避免疫杀伤。机会性人类真菌病原体白色念珠菌被巨噬细胞有效吞噬，但会引发炎症小体激活、宿主细胞溶解，并在形成菌丝后逃脱。先前的研究表明，白色念珠菌引起的巨噬细胞裂解是由于早期炎症小体依赖性细胞死亡（细胞焦亡），以及由于葡萄糖耗竭和生长菌丝刺穿细胞膜引起的晚期损伤。在这里，我们表明，细胞溶解素，一种由菌丝相关基因 ECE1 编码的细胞溶解肽毒素，是 NLRP3 炎症小体依赖性半胱天冬酶-1 激活的核心触发因素，通过钾外排，并且是白色念珠菌感染时巨噬细胞和树突状细胞炎症小体非依赖性细胞溶解的关键驱动因素。这表明，细胞溶解素诱导的细胞损伤是白色念珠菌介导的单核吞噬细胞死亡的除细胞焦亡和葡萄糖消耗菌丝生长引起的损伤之外的第三种机制。
