C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling.

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  • Additional Information
    • Source:
      Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE
    • Publication Information:
      Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]-
    • Subject Terms:
      Critical Illness* ; Phagocytosis*; Complement C5a/*metabolism ; Neutrophils/*pathology ; Phagosomes/*physiology ; Phosphoproteins/*metabolism ; Staphylococcal Infections/*pathology; Case-Control Studies ; Humans ; Neutrophils/immunology ; Neutrophils/metabolism ; Neutrophils/microbiology ; Phagosomes/microbiology ; Proteome ; Staphylococcal Infections/immunology ; Staphylococcal Infections/metabolism ; Staphylococcal Infections/microbiology ; Staphylococcus aureus/physiology
    • 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.
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    • Grant Information:
      United Kingdom BHF_ British Heart Foundation; 205214/Z/16/Z United Kingdom WT_ Wellcome Trust; MR/N02995X/1 United Kingdom MRC_ Medical Research Council; MR/ N02995X/1 United Kingdom MRC_ Medical Research Council; WT 2055214/Z/16/Z United Kingdom WT_ Wellcome Trust; United Kingdom WT_ Wellcome Trust
    • Contributed Indexing:
      Keywords: Bacterial infections; Complement; Immunology; Infectious disease; Neutrophils
    • Accession Number:
      0 (Phosphoproteins)
      0 (Proteome)
      80295-54-1 (Complement C5a)
    • Publication Date:
      Date Created: 20200708 Date Completed: 20210531 Latest Revision: 20220317
    • Publication Date:
      20231215
    • Accession Number:
      PMC7455072
    • Accession Number:
      10.1172/jci.insight.137029
    • Accession Number:
      32634128