A type I IFN, prothrombotic hyperinflammatory neutrophil signature is distinct for COVID-19 ARDS

Wellcome Open Research

article

Leila Reyes¹  Manuel A. Sanchez-Garcia¹  Tyler Morrison¹  Andy J. M. Howden²  Emily R. Watts¹  Simone Arienti¹  Pranvera Sadiku¹  Patricia Coelho¹  Ananda S. Mirchandani¹  Ailiang Zhang¹  David Hope³  Sarah K. Clark³  Jo Singleton³  Shonna Johnston¹  Robert Grecian¹  Azin Poon¹  Sarah McNamara¹  Isla Harper¹  Max Head Fourman³  Alejandro J. Brenes²  Shalini Pathak²  Amy Lloyd²  Giovanny Rodriguez Blanco⁵  Alex von Kriegsheim⁵  Bart Ghesquiere⁶  Wesley Vermaelen⁶  Camila T. Cologna⁶  Kevin Dhaliwal¹  Nik Hirani¹  David H. Dockrell¹  Moira K. B. Whyte¹  David Griffith³  Doreen A. Cantrell²  Sarah R. Walmsley¹ 

[1] Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh;Division of Cell Signalling and Immunology, University of Dundee;Anaesthesia, Critical Care and Pain, University of Edinburgh, Royal Infirmary of Edinburgh;Centre for Gene Regulation and Expression, University of Dundee;The University of Edinburgh MRC Institute of Genetics and Molecular Medicine, University of Edinburgh;Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre;NHS Lothian, Respiratory Medicine, Edinburgh Lung Fibrosis Clinic, Royal Infirmary

关键词: Neutrophil;    SARS-CoV-2;    COVID-19;    ARDS;    Type I IFN;    dexamethasone;   

DOI  :  10.12688/wellcomeopenres.16584.2

学科分类：内科医学

来源: Wellcome

【 摘 要 】

Background: Acute respiratory distress syndrome (ARDS) is a severe critical condition with a high mortality that is currently in focus given that it is associated with mortality caused by coronavirus disease 2019 (COVID-19). Neutrophils play a key role in the lung injury characteristic of non-COVID-19 ARDS and there is also accumulating evidence of neutrophil mediated lung injury in patients who succumb to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Methods: We undertook a functional proteomic and metabolomic survey of circulating neutrophil populations, comparing patients with COVID-19 ARDS and non-COVID-19 ARDS to understand the molecular basis of neutrophil dysregulation.Results: Expansion of the circulating neutrophil compartment and the presence of activated low and normal density mature and immature neutrophil populations occurs in ARDS, irrespective of cause. Release of neutrophil granule proteins, neutrophil activation of the clotting cascade and upregulation of the Mac-1 platelet binding complex with formation of neutrophil platelet aggregates is exaggerated in COVID-19 ARDS. Importantly, activation of components of the neutrophil type I interferon responses is seen in ARDS following infection with SARS-CoV-2, with associated rewiring of neutrophil metabolism, and the upregulation of antigen processing and presentation. Whilst dexamethasone treatment constricts the immature low density neutrophil population, it does not impact upon prothrombotic hyperinflammatory neutrophil signatures.Conclusions: Given the crucial role of neutrophils in ARDS and the evidence of a disordered myeloid response observed in COVID-19 patients, this work maps the molecular basis for neutrophil reprogramming in the distinct clinical entities of COVID-19 and non-COVID-19 ARDS.

【 授权许可】

CC BY