C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection

  • Cell. 2023 May 18;S0092-8674(23)00465-8. doi: 10.1016/j.cell.2023.04.031.
Jigar V Desai  1 ,  Dhaneshwar Kumar  2 ,  Tilo Freiwald  3 ,  Daniel Chauss  3 ,  Melissa D Johnson  4 ,  Michael S Abers  1 ,  Julie M Steinbrink  5 ,  John R Perfect  5 ,  Barbara Alexander  5 ,  Vasiliki Matzaraki  6 ,  Brendan D Snarr  1 ,  Marissa A Zarakas  1 ,  Vasileios Oikonomou  1 ,  Lakmali M Silva  7 ,  Raju Shivarathri  8 ,  Emily Beltran  9 ,  Luciana Negro Demontel  9 ,  Luopin Wang  10 ,  Jean K Lim  11 ,  Dylan Launder  12 ,  Heather R Conti  12 ,  Muthulekha Swamydas  1 ,  Micah T McClain  5 ,  Niki M Moutsopoulos  7 ,  Majid Kazemian  10 ,  Mihai G Netea  13 ,  Vinod Kumar  14 ,  Jörg Köhl  15 ,  Claudia Kemper  9 ,  Behdad Afzali  3 ,  Michail S Lionakis  16
Affiliations
  • 1. Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases, NIH, Bethesda, MD, USA.
  • 2. Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA; Departments of Biochemistry and Computer Science, Purdue University, West Lafayette, IN, USA.
  • 3. Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA.
  • 4. Duke Clinical Research Institute, Durham, NC, USA.
  • 5. Department of Medicine, Division of Infectious Diseases, Duke University, Durham, NC, USA.
  • 6. Department of Genetics, University of Groningen, Groningen, the Netherlands.
  • 7. Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
  • 8. Center for Discovery & Innovation, Hackensack Meridian Health, Nutley, NJ, USA.
  • 9. Complement and Inflammation Research Section, National Heart Lung and Blood Institute, NIH, Bethesda, MD, USA.
  • 10. Departments of Biochemistry and Computer Science, Purdue University, West Lafayette, IN, USA.
  • 11. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 12. Department of Biological Sciences, University of Toledo, Toledo, OH, USA.
  • 13. Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University, Nijmegen, the Netherlands.
  • 14. Department of Genetics, University of Groningen, Groningen, the Netherlands; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University, Nijmegen, the Netherlands.
  • 15. Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
  • 16. Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases, NIH, Bethesda, MD, USA. Electronic address: [email protected].
PMID: 37220746 DOI: 10.1016/j.cell.2023.04.031
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.

Keywords
C5; C5aR1; Candida; avacopan; candidemia; candidiasis; complement; eculizumab; kidney.
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