C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection

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 LaunderHeather R. Conti, Muthulekha Swamydas, Micah T. McClain, Niki M. Moutsopoulos, Majid Kazemian, Mihai G. Netea, Vinod Kumar, Jörg Köhl, Claudia Kemper, Behdad Afzali, Michail S. Lionakis

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish
Pages (from-to)2802-2822.e22
JournalCell
Volume186
Issue number13
DOIs
StatePublished - 22 Jun 2023

Keywords

  • C5
  • C5aR1
  • Candida
  • avacopan
  • candidemia
  • candidiasis
  • complement
  • eculizumab
  • kidney

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