C5a-licensed Phagocytes Drive Sterilizing Immunity During Systemic Fungal Infection

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2023 May 23

PMID 37220746

Authors

Jigar V Desai

Dhaneshwar Kumar

Tilo Freiwald

Daniel Chauss

Melissa D Johnson

Michael S Abers

Julie M Steinbrink

John R Perfect

Barbara Alexander

Vasiliki Matzaraki

Brendan D Snarr

Marissa A Zarakas

Vasileios Oikonomou

Lakmali M Silva

Raju Shivarathri

Emily Beltran

Luciana Negro Demontel

Luopin Wang

Jean K Lim

Dylan Launder

Heather R Conti

Muthulekha Swamydas

Micah T McClain

Niki M Moutsopoulos

Majid Kazemian

Mihai G Netea

Vinod Kumar

Jorg Kohl

Claudia Kemper

Behdad Afzali

Michail S Lionakis

Affiliations

Soon will be listed here.

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 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.

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