Dysregulated neutrophil phenotype and function in hospitalised non-ICU COVID-19 pneumonia

Kylie B. R. Belchamber, Onn Shaun Thein, Jon Hazeldine, Frances S. Grudzinska, Aduragbemi Faniyi, Michael Hughes, Alice Jasper, Kay Por Yip, Louise E. Crowley, Sebastian T. Lugg, Elizabeth Sapey, Dhruv Parekh, David R. Thickett, Aaron Scott

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Abstract

Rationale: Infection with the SARS-CoV2 virus is associated with elevated neutrophil counts. Evidence of neutrophil dysfunction in COVID-19 is based on transcriptomics or single functional assays. Cell functions are interwoven pathways, and understanding the effect across the spectrum of neutrophil function may identify therapeutic targets.

Objectives: Examine neutrophil phenotype and function in 41 hospitalised, non-ICU COVID-19 patients versus 23 age-matched controls (AMC) and 26 community acquired pneumonia patients (CAP).

Methods: Isolated neutrophils underwent ex vivo analyses for migration, bacterial phagocytosis, ROS generation, NETosis and receptor expression. Circulating DNAse 1 activity, levels of cfDNA, MPO, VEGF, IL-6 and sTNFRI were measured and correlated to clinical outcome. Serial sampling on day three to five post hospitalization were also measured. The effect of ex vivo PI3K inhibition was measured in a further cohort of 18 COVID-19 patients.

Results: Compared to AMC and CAP, COVID-19 neutrophils demonstrated elevated transmigration (p = 0.0397) and NETosis (p = 0.0332), and impaired phagocytosis (p = 0.0036) associated with impaired ROS generation (p < 0.0001). The percentage of CD54+ neutrophils (p < 0.001) was significantly increased, while surface expression of CD11b (p = 0.0014) and PD-L1 (p = 0.006) were significantly decreased in COVID-19. COVID-19 and CAP patients showed increased systemic markers of NETosis including increased cfDNA (p = 0.0396) and impaired DNAse activity (p < 0.0001). The ex vivo inhibition of PI3K γ and δ reduced NET release by COVID-19 neutrophils (p = 0.0129).

Conclusions: COVID-19 is associated with neutrophil dysfunction across all main effector functions, with altered phenotype, elevated migration and NETosis, and impaired antimicrobial responses. These changes highlight that targeting neutrophil function may help modulate COVID-19 severity.
Original languageEnglish
Article number2901
Number of pages20
JournalCells
Volume11
Issue number18
DOIs
Publication statusPublished - 16 Sept 2022

Bibliographical note

Funding Information:
O.S.T./D.T./D.P.: Birmingham Health partners, K.B.R.B./E.S.; Alpha One Foundation (617303), M.J.H.; National Institute for Health Research (NIHR) Surgical Reconstruction and Microbiology Research Centre, E.S./K.Y.P.; Asthma + Lung UK, D.T./A.S./E.S./F.S.G.; Dunhill trust (RTF1906\86), E.S.; Health Data Research-UK, D.T./D.P.; Health Technology Assessment, D.T./A.S./E.S./D.P.; Health Technology Assessment (NIHR129593), A.S./D.T./E.S./D.P.; Efficacy and Mechanism Evaluation (NIHR131600) D.T./A.S./E.S.; Medical Research Council (MR/L002782/1).

J.H. is supported by the National Institute for Health Research (NIHR) Surgical Reconstruction and Microbiology Research Centre (SRMRC). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Special thanks to UK-Coronavirus immunology consortium, and to the University of Birmingham Flow Cytometry Core.

Publisher Copyright:
© 2022 by the authors.

Keywords

  • inflammation
  • COVID-19
  • neutrophil
  • innate immunity

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology

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