期刊
JCI INSIGHT
卷 5, 期 15, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.137029
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资金
- Cambridge NIHR BRC Cell Phenotyping Hub
- Cambridge NIHR Biomedical Research Centre
- Gates Cambridge Trust
- Clinical Research Career Development Fellowship from the Wellcome Trust [WT 2055214/Z/16/Z]
- Academy of Medical Sciences
- European Society for Intensive Care Medicine
- National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre [IS-BRC-1215-20001]
- Medical Research Council SHIELD antimicrobial resistance consortium [MR/N02995X/1]
- Medical Research Council
- Wellcome Trust
- NIHR Imperial Biomedical Research Centre
- GlaxoSmithKline
- British Heart Foundation
- MedImmune
- BristolMyersSquibb
- National Institutes of Health Research (NIHR) [IS-BRC-1215-20001] Funding Source: National Institutes of Health Research (NIHR)
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 oureus. Phosphoproteomic profiling of 2712 phosphoproteins identified persistent C5a signaling and selective impairment of phagosomal protein phosphorylation on exposureto S. oureus. 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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