Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA.
Department of Burn and Plastic Surgery, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China.
Nat Commun. 2021 Nov 18;12(1):6699. doi: 10.1038/s41467-021-27034-9.
Candida albicans is the most common cause of fungal sepsis. Inhibition of inflammasome activity confers resistance to polymicrobial and LPS-induced sepsis; however, inflammasome signaling appears to protect against C. albicans infection, so inflammasome inhibitors are not clinically useful for candidiasis. Here we show disruption of GSDMD, a known inflammasome target and key pyroptotic cell death mediator, paradoxically alleviates candidiasis, improving outcomes and survival of Candida-infected mice. Mechanistically, C. albicans hijacked the canonical inflammasome-GSDMD axis-mediated pyroptosis to promote their escape from macrophages, deploying hyphae and candidalysin, a pore-forming toxin expressed by hyphae. GSDMD inhibition alleviated candidiasis by preventing C. albicans escape from macrophages while maintaining inflammasome-dependent but GSDMD-independent IL-1β production for anti-fungal host defenses. This study demonstrates key functions for GSDMD in Candida's escape from host immunity in vitro and in vivo and suggests that GSDMD may be a potential therapeutic target in C. albicans-induced sepsis.
白色念珠菌是真菌性败血症最常见的病因。抑制炎症小体的活性可抵抗多微生物和 LPS 诱导的败血症；然而，炎症小体信号似乎可以保护机体免受白色念珠菌感染，因此炎症小体抑制剂在临床上对念珠菌病没有用处。在这里，我们发现，作为已知的炎症小体靶点和关键的细胞焦亡死亡介质的 GSDMD 发生中断，会出人意料地缓解念珠菌病，改善感染白色念珠菌的小鼠的预后和存活率。从机制上讲，白色念珠菌劫持了经典炎症小体-GSDMD 轴介导的细胞焦亡，以促进其从巨噬细胞中逃逸，同时利用菌丝和菌丝表达的一种形成孔的毒素——白念珠菌溶血素。GSDMD 抑制通过防止白色念珠菌从巨噬细胞中逃逸来缓解念珠菌病，同时保持炎症小体依赖性但 GSDMD 非依赖性的抗真菌宿主防御的 IL-1β 产生。这项研究表明 GSDMD 在白色念珠菌体外和体内逃避宿主免疫方面具有重要功能，并表明 GSDMD 可能是白色念珠菌诱导的败血症的一个潜在治疗靶点。
