C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection

Desai, Jigar V; Kumar, Dhaneshwar; Freiwald, Tilo; Chauss, Daniel; Johnson, Melissa D; Abers, Michael S; Steinbrink, Julie M; Perfect, John R; Alexander, Barbara; Matzaraki, Vasiliki; Snarr, Brendan D; Zarakas, Marissa A; Oikonomou, Vasileios; Silva, Lakmali M; Shivarathri, Raju; Beltran, Emily; Demontel, Luciana Negr N; Wang, Luopin; Lim, Jean K; Launder, Dylan; Conti, Heather R; Swamydas, Muthulekha; McClain, Micah T; Moutsopoulos, Niki M; Kazemian, Majid; Netea, Mihai G; Kumar, Vinod; Köhl, Jörg; Kemper, Claudia; Afzali, Behdad; Lionakis, Michail S

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.

C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection Article (Faculty180)