TY - JOUR
T1 - C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection
AU - Desai, Jigar V.
AU - Kumar, Dhaneshwar
AU - Freiwald, Tilo
AU - Chauss, Daniel
AU - Johnson, Melissa D.
AU - Abers, Michael S.
AU - Steinbrink, Julie M.
AU - Perfect, John R.
AU - Alexander, Barbara
AU - Matzaraki, Vasiliki
AU - Snarr, Brendan D.
AU - Zarakas, Marissa A.
AU - Oikonomou, Vasileios
AU - Silva, Lakmali M.
AU - Shivarathri, Raju
AU - Beltran, Emily
AU - Demontel, Luciana Negro
AU - Wang, Luopin
AU - Lim, Jean K.
AU - Launder, Dylan
AU - Conti, Heather R.
AU - Swamydas, Muthulekha
AU - McClain, Micah T.
AU - Moutsopoulos, Niki M.
AU - Kazemian, Majid
AU - Netea, Mihai G.
AU - Kumar, Vinod
AU - Köhl, Jörg
AU - Kemper, Claudia
AU - Afzali, Behdad
AU - Lionakis, Michail S.
N1 - Publisher Copyright:
© 2023
PY - 2023/6/22
Y1 - 2023/6/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85162129479&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/c666089a-a7d8-3f2f-96b7-31b260f840f0/
U2 - 10.1016/j.cell.2023.04.031
DO - 10.1016/j.cell.2023.04.031
M3 - Journal articles
C2 - 37220746
AN - SCOPUS:85162129479
SN - 0092-8674
VL - 186
SP - 2802-2822.e22
JO - Cell
JF - Cell
IS - 13
ER -