1. Academic Validation
  2. C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection

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

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: lionakism@mail.nih.gov.
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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