Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling
Alexander J.T. Wood, … , Klaus Okkenhaug, Andrew Conway Morris
Alexander J.T. Wood, … , Klaus Okkenhaug, Andrew Conway Morris
Published July 7, 2020
Citation Information: JCI Insight. 2020;5(15):e137029. https://doi.org/10.1172/jci.insight.137029.
View: Text | PDF
Research Article Immunology Infectious disease

C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling

  • Text
  • PDF
Abstract

Critical illness is accompanied by the release of large amounts of the anaphylotoxin, C5a. C5a suppresses antimicrobial functions of neutrophils which is associated with adverse outcomes. The signaling pathways that mediate C5a-induced neutrophil dysfunction are incompletely understood. Healthy donor neutrophils exposed to purified C5a demonstrated a prolonged defect (7 hours) in phagocytosis of Staphylococcus aureus. Phosphoproteomic profiling of 2712 phosphoproteins identified persistent C5a signaling and selective impairment of phagosomal protein phosphorylation on exposure to S. aureus. Notable proteins included early endosomal marker ZFYVE16 and V-ATPase proton channel component ATPV1G1. An assay of phagosomal acidification demonstrated C5a-induced impairment of phagosomal acidification, which was recapitulated in neutrophils from critically ill patients. Examination of the C5a-impaired protein phosphorylation indicated a role for the PI3K VPS34 in phagosomal maturation. Inhibition of VPS34 impaired neutrophil phagosomal acidification and killing of S. aureus. This study provides a phosphoproteomic assessment of human neutrophil signaling in response to S. aureus and its disruption by C5a, identifying a defect in phagosomal maturation and mechanisms of immune failure in critical illness.

Authors

Alexander J.T. Wood, Arlette M. Vassallo, Marie-Hélène Ruchaud-Sparagano, Jonathan Scott, Carmelo Zinnato, Carmen Gonzalez-Tejedo, Kamal Kishore, Clive S. D’Santos, A. John Simpson, David K. Menon, Charlotte Summers, Edwin R. Chilvers, Klaus Okkenhaug, Andrew Conway Morris

×

Graphical abstract

Options: View larger image (or click on image)

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts