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C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection.
Desai, Jigar V; Kumar, Dhaneshwar; Freiwald, Tilo; Chauss, Daniel; Johnson, Melissa D; Abers, Michael S; Steinbrink, Julie M; Perfect, John R; Alexander, Barbara; Matzaraki, Vasiliki; Snarr, Brendan D; Zarakas, Marissa A; Oikonomou, Vasileios; Silva, Lakmali M; Shivarathri, Raju; Beltran, Emily; Demontel, Luciana Negro; Wang, Luopin; Lim, Jean K; Launder, Dylan; Conti, Heather R; Swamydas, Muthulekha; McClain, Micah T; Moutsopoulos, Niki M; Kazemian, Majid; Netea, Mihai G; Kumar, Vinod; Köhl, Jörg; Kemper, Claudia; Afzali, Behdad; Lionakis, Michail S.
  • Desai JV; Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases, NIH, Bethesda, MD, USA.
  • Kumar D; 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.
  • Freiwald T; Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA.
  • Chauss D; Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA.
  • Johnson MD; Duke Clinical Research Institute, Durham, NC, USA.
  • Abers MS; Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases, NIH, Bethesda, MD, USA.
  • Steinbrink JM; Department of Medicine, Division of Infectious Diseases, Duke University, Durham, NC, USA.
  • Perfect JR; Department of Medicine, Division of Infectious Diseases, Duke University, Durham, NC, USA.
  • Alexander B; Department of Medicine, Division of Infectious Diseases, Duke University, Durham, NC, USA.
  • Matzaraki V; Department of Genetics, University of Groningen, Groningen, the Netherlands.
  • Snarr BD; Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases, NIH, Bethesda, MD, USA.
  • Zarakas MA; Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases, NIH, Bethesda, MD, USA.
  • Oikonomou V; Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases, NIH, Bethesda, MD, USA.
  • Silva LM; Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
  • Shivarathri R; Center for Discovery & Innovation, Hackensack Meridian Health, Nutley, NJ, USA.
  • Beltran E; Complement and Inflammation Research Section, National Heart Lung and Blood Institute, NIH, Bethesda, MD, USA.
  • Demontel LN; Complement and Inflammation Research Section, National Heart Lung and Blood Institute, NIH, Bethesda, MD, USA.
  • Wang L; Departments of Biochemistry and Computer Science, Purdue University, West Lafayette, IN, USA.
  • Lim JK; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Launder D; Department of Biological Sciences, University of Toledo, Toledo, OH, USA.
  • Conti HR; Department of Biological Sciences, University of Toledo, Toledo, OH, USA.
  • Swamydas M; Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases, NIH, Bethesda, MD, USA.
  • McClain MT; Department of Medicine, Division of Infectious Diseases, Duke University, Durham, NC, USA.
  • Moutsopoulos NM; Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
  • Kazemian M; Departments of Biochemistry and Computer Science, Purdue University, West Lafayette, IN, USA.
  • Netea MG; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University, Nijmegen, the Netherlands.
  • Kumar V; Department of Genetics, University of Groningen, Groningen, the Netherlands; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University, Nijmegen, the Netherlands.
  • Köhl J; Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
  • Kemper C; Complement and Inflammation Research Section, National Heart Lung and Blood Institute, NIH, Bethesda, MD, USA.
  • Afzali B; Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA.
  • Lionakis MS; Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases, NIH, Bethesda, MD, USA. Electronic address: lionakism@mail.nih.gov.
Cell ; 186(13): 2802-2822.e22, 2023 06 22.
Article en En | MEDLINE | ID: mdl-37220746
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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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Candidiasis / Antifúngicos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Año: 2023 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Candidiasis / Antifúngicos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Año: 2023 Tipo del documento: Article