Cell · 2023
C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection.
СтатьяResearch Support, N.I.H., IntramuralПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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 Negro, 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
Аннотация
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.