C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling
| Autor: | David K. Menon, Charlotte Summers, Edwin R. Chilvers, Alexander J.T. Wood, Carmelo Zinnato, A. John Simpson, Jonathan Scott, Kamal Kishore, Carmen Gonzalez-Tejedo, Andrew Conway Morris, Clive D'Santos, Klaus Okkenhaug, Marie-Hélène Ruchaud-Sparagano, Arlette Vassallo |
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| Přispěvatelé: | Kishore, Kamal [0000-0002-4650-8745], Menon, David [0000-0002-3228-9692], Summers, Charlotte [0000-0002-7269-2873], Okkenhaug, Klaus [0000-0002-9432-4051], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Staphylococcus aureus Proteome Endosome Neutrophils Phagocytosis Critical Illness Immunology Complement Complement C5a chemical and pharmacologic phenomena medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Immune system Bacterial infections Phagosomes medicine Humans Protein phosphorylation PI3K/AKT/mTOR pathway Infectious disease Chemistry Critically ill FOS: Clinical medicine hemic and immune systems General Medicine Staphylococcal Infections Phosphoproteins 3. Good health Cell biology 030104 developmental biology 030220 oncology & carcinogenesis Case-Control Studies Signal transduction Research Article |
| Zdroj: | JCI Insight |
| Popis: | 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. C5a disrupts the neutrophil phosphoproteomic response to bacteria, impairing phagosomal maturation and bacterial killing. |
| Databáze: | OpenAIRE |
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