Complement C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodelling
| Autor: | Klaus Okkenhaug, Clive D'Santos, Charlotte Summers, Marie-Hélène Ruchaud-Sparagano, Jonathan M. Scott, Andrew Conway Morris, A. John Simpson, David K. Menon, Arlette Vassallo, Alex J. Wood, Carmelo Zinnato, Kamal Kishore, Edwin R. Chilvers, Carmen Gonzalez-Tejedo |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Endosome Phagocytosis hemic and immune systems chemical and pharmacologic phenomena Complement C5a medicine.disease_cause Cell biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immune system chemistry Staphylococcus aureus medicine Neutrophil dysfunction Protein phosphorylation Phosphatidylinositol 030304 developmental biology 030215 immunology |
| DOI: | 10.1101/2020.01.17.907618 |
| 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 signalling 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. 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 signalling 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 signalling 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. A novel 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 phosphatidylinositol 3-kinase 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 signalling in response to S. aureus and its disruption by C5a, identifying a defect in phagosomal maturation and new mechanisms of immune failure in critical illness. |
| Databáze: | OpenAIRE |
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