Dysregulated Neutrophil Phenotype and Function in Hospitalised Non-ICU COVID-19 Pneumonia
Kylie B. R. Belchamber,
Onn S. Thein,
Jon Hazeldine,
Frances S. Grudzinska,
Aduragbemi A. Faniyi,
Michael J. Hughes,
Alice E. Jasper,
Kay Por Yip,
Louise E. Crowley,
Sebastian T. Lugg,
Elizabeth Sapey,
Dhruv Parekh,
David R. Thickett,
Aaron Scott
Affiliations
Kylie B. R. Belchamber
Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK
Onn S. Thein
Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK
Jon Hazeldine
National Institute for Health Research Surgical Reconstruction and Microbiology Research Centre, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, UK
Frances S. Grudzinska
Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK
Aduragbemi A. Faniyi
Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK
Michael J. Hughes
Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK
Alice E. Jasper
Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK
Kay Por Yip
Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK
Louise E. Crowley
Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK
Sebastian T. Lugg
Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK
Elizabeth Sapey
Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK
Dhruv Parekh
Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK
David R. Thickett
Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK
Aaron Scott
Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK
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 p 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 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.
