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 pro-moted 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 macro-phage 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 produc-tion licenses phagocyte antimicrobial function and confers innate protection during systemic fungal infection.
C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection
Oikonomou, Vasileios;
2023
Abstract
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 pro-moted 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 macro-phage 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 produc-tion licenses phagocyte antimicrobial function and confers innate protection during systemic fungal infection.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
