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

Abstract

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.

A functionally distinct neutrophil landscape in severe COVID-19 reveals opportunities for adjunctive therapies

“…In particular, we found that dexamethasone treatment did not modulate the functional landscape of neutrophils or attenuate the production of NETs. This is in line with a publication suggesting that dexamethasone does not alter the NET-related neutrophil proteome in patients with severe COVID-19 ( 28 ). Of note, our findings do not rule out the possibility that dexamethasone modulates other aspects of neutrophil development or activation in vivo, as has been suggested using transcriptomic analysis of the circulating neutrophil pool in severe COVID-19 ( 29 ).…”

Differential Functional Responses of Neutrophil Subsets in Severe COVID-19 Patients

“…Neutrophil characterization by transcriptional and proteomic analysis in COVID-19 indicates significant heterogeneity among mature neutrophils and emergence of a large number of low density neutrophils (LDN) with multiple phenotypes ( 16 , 24 , 25 , 27 – 30 ). The functional capability of these various neutrophil populations has been inferred from gene or protein expression profiles ( 22 – 26 ), however, previous direct functional studies either did not evaluate the various neutrophil populations or disparate results were reported ( 12 – 15 , 24 , 28 – 37 ). Thus, the functional heterogeneity among the various neutrophil populations remains to be defined.…”

Physiological and Pathophysiological Roles of Metabolic Pathways for NET Formation and Other Neutrophil Functions

“…The increased glycolytic activity of COVID-19 neutrophils might provide a mechanistic explanation for the increased spontaneous NET formation by neutrophils isolated from patients with severe COVID-19 (209,210). However, contrasting results have also been reported that suggested an impaired glycolytic flow and oxidative metabolism in neutrophils isolated from COVID-19 patients with ARDS symptoms (223). Currently, the reasons for these different findings remain unclear.…”