Systemic candidiasis is a common, high-mortality, nosocomial fungal infection. Unexpectedly, it has emerged as a complication of anti-complement C5-targeted monoclonal antibody treatment, indicating a critical niche for C5 in antifungal immunity. We identified transcription of complement system genes as the top biological pathway induced in candidemic patients and as predictive of candidemia. Mechanistically, C5a-C5aR1 promoted fungal clearance and host survival in a mouse model of systemic candidiasis by stimulating phagocyte effector function and ERK- and AKT-dependent survival in infected tissues. C5ar1 ablation rewired macrophage metabolism downstream of mTOR, promoting their apoptosis and enhancing mortality through kidney injury. Besides hepatocyte-derived C5, local C5 produced intrinsically by phagocytes provided a key substrate for antifungal protection. Lower serum C5a concentrations or a C5 polymorphism that decreases leukocyte C5 expression correlated independently with poor patient outcomes. Thus, local, phagocyte-derived C5 production licenses phagocyte antimicrobial function and confers innate protection during systemic fungal infection.

系统性念珠菌病是一种常见的、高死亡率的医院内真菌感染。出乎意料的是，它已成为抗补体 C5 靶向单克隆抗体治疗的并发症，表明 C5 在抗真菌免疫中的关键地位。我们确定补体系统基因的转录是念珠菌血症患者中诱导的首要生物途径，并且可以预测念珠菌血症。从机制上讲，C5a-C5aR1 通过刺激感染组织中的吞噬细胞效应器功能以及 ERK 和 AKT 依赖性存活来促进系统性念珠菌病小鼠模型中的真菌清除和宿主存活。C5ar1消融重新连接了 mTOR 下游的巨噬细胞代谢，促进其凋亡并通过肾损伤提高死亡率。除了肝细胞来源的 C5 之外，吞噬细胞本身产生的局部 C5 也提供了抗真菌保护的关键底物。较低的血清C5a 浓度或降低白细胞 C5 表达的 C5 多态性与不良患者预后独立相关。因此，局部吞噬细胞衍生的 C5 生产许可吞噬细胞抗菌功能，并在全身真菌感染期间提供先天保护。