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C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling

Lookup NU author(s): Dr Marie Ruchaud-Sparagano, Dr Jonathan Scott, Professor John Simpson

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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.


Publication metadata

Author(s): Wood AJ, Vassallo AM, Ruchaud-Sparagano M-H, Scott J, Zinnato C, Gonzalez-Tejedo C, Kishore K, D'Santos CS, Simpson AJ, Menon DK, Summers C, Chilvers ER, Okkenhaug K, Morris AC

Publication type: Article

Publication status: Published

Journal: JCI insight

Year: 2020

Volume: 5

Issue: 15

Print publication date: 06/08/2020

Online publication date: 07/07/2020

Acceptance date: 24/06/2020

Date deposited: 17/08/2020

ISSN (electronic): 2379-3708

Publisher: American Society for Clinical Investigation

URL: https://doi.org/10.1172/jci.insight.137029

DOI: 10.1172/jci.insight.137029

PubMed id: 32634128


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