Summary
Understanding the mechanisms by which infection with SARS-CoV-2 leads to acute respiratory distress syndrome (ARDS) is of significant clinical interest given the mortality associated with severe and critical coronavirus induced disease 2019 (COVID-19). Neutrophils play a key role in the lung injury characteristic of non-COVID-19 ARDS, but a relative paucity of these cells is observed at post-mortem in lung tissue of patients who succumb to infection with SARS-CoV-2. With emerging evidence of a dysregulated innate immune response in COVID-19, we undertook a functional proteomic survey of circulating neutrophil populations, comparing patients with COVID-19 ARDS, non-COVID-19 ARDS, moderate COVID-19, and healthy controls. We observe that expansion of the circulating neutrophil compartment and the presence of activated low and normal density mature and immature neutrophil populations occurs in both COVID-19 and non-COVID-19 ARDS. In contrast, release of neutrophil granule proteins, neutrophil activation of the clotting cascade and formation of neutrophil platelet aggregates is significantly increased in COVID-19 ARDS. Importantly, activation of components of the neutrophil type I IFN responses is specific to infection with SARS-CoV-2 and linked to metabolic rewiring. Together this work highlights how differential activation of circulating neutrophil populations may contribute to the pathogenesis of ARDS, identifying processes that are specific to COVID-19 ARDS.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
This research was supported by a Wellcome Trust Senior Clinical Fellowship award (209220) and a CRUK cancer immunology project award (C62207/A24495) to S.R.W, Wellcome Clinical training Fellowship awards to T.M. (214383/Z/18/Z) and E.R.W (108717/Z/15/Z), a Wellcome Trust Post-doctoral Training Clinical Fellowship awarded to A.S.M (110086), a Medical Research Foundation PhD Studentship to S.A., UKRI/NIHR funding through the UK Coronavirus Immunology Consortium (UK-CIC) and a CSO grant (COV/DUN/20/01) to D.A.C, and a LifeArc STOPCOVID award to A.P and S.M.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
Human peripheral venous blood was taken from healthy volunteers with written informed consent obtained from all participants prior to sample collection as approved by the University of Edinburgh Centre for Inflammation Research Blood Resource Management Committee (AMREC 15-HV-013). The collection of peripheral venous blood from male or female patients diagnosed with COVID-19 and/or presenting with ARDS was approved by Scotland A Research Ethics Committee. Patient recruitment took place from April 2020 through August 2020 from The Royal Infirmary of Edinburgh, Scotland, UK through the ARDS Neut (20/SS/0002) and CASCADE (20/SS/0052) Study, with informed consent obtained by proxy.
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