S54 Elevated NETosis and migration but impaired anti-microbial responses in neutrophils from non-ICU, hospitalized COVID-19 patients

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Abstract

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

Objectives Examine neutrophil phenotype and functional capacity in COVID-19 patients versus age-matched controls (AMC).

Methods Isolated neutrophils from 41 non-ICU COVID-19 patients and 23 AMC underwent ex vivo analyses for migration, phagocytosis of Streptococcus pneumoniae, reactive oxygen species (ROS) generation, neutrophil extracellular trap formation (NETosis) and cell surface receptor expression. Serum DNAse 1 activity was measured, alongside circulating levels of cell-free (cf)DNA, myeloperoxidase (MPO), VEGF, IL-6 and sTNFRI. All measurements were correlated to clinical outcome. Serial sampling on day 3–5 post hospitalisation were also measured.

Results Compared to AMC, COVID-19 neutrophils demonstrated elevated transmigration (p=0.0397) and NETosis (p=0.0366), but impaired phagocytosis (p=0.0236) associated with impaired ROS generation (p<0.0001). Surface expression of CD54 (p<0.0001) and CD11c (p=0.0008) was significantly increased and CD11b significantly decreased (p=0.0229) on COVID-19 patient neutrophils. On day 3–5 follow-up, levels of senescent neutrophils increased compared to day 1 (indicated by decreased CXCR2 and elevated CXCR4 expression (p=0.0332)). COVID-19 patients showed increased systemic markers of NETosis including increased cfDNA (p=0.0153) and impaired DNAse activity (p<0.0.001). MPO, VEGF, sTNFRI, and IL-6 (p<0001) were elevated in COVID-19, which positively correlated with disease severity by 4C score.

Conclusion COVID-19 is associated with neutrophil dysfunction across all main effector functions, with altered phenotype, elevated migration, impaired antimicrobial responses and elevated NETosis. These changes represent a clear mechanism for tissue damage and highlight that targeting neutrophil function may help modulate COVID-19 severity.
Original languageEnglish
Pages (from-to)A37
JournalThorax
Volume76
Issue numberSuppl 2
DOIs
Publication statusPublished - 8 Nov 2021

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