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

Abstract

Acute respiratory distress syndrome (ARDS) is a life-threatening syndrome of respiratory failure and diffuse alveolar damage that results from dysregulated local and systemic immune activation, causing pulmonary vascular, parenchymal and alveolar damage. SARS-CoV-2 infection has become the dominant cause of ARDS worldwide, and emerging evidence implicates neutrophils and their cytotoxic arsenal of effector functions as central drivers of immune-mediated lung injury in COVID-19 ARDS. However, a key outstanding question is whether COVID-19 drives a unique program of neutrophil activation or effector functions that contributes to the severe pathogenesis of this pandemic illness, and whether this unique neutrophil response can be targeted to attenuate disease. Using a combination of high-dimensional single cell analysis and ex vivo functional assays of neutrophils from patients with COVID-19 ARDS compared to non-COVID ARDS (caused by bacterial pneumonia), we identified a functionally distinct landscape of neutrophil activation in COVID-19 ARDS that was intrinsically programmed during SARS-CoV-2 infection. Furthermore, neutrophils in COVID-19 ARDS were functionally primed to produce high amounts of neutrophil extracellular traps (NETs). Surprisingly, this unique pathological program of neutrophil priming escaped conventional therapy with dexamethasone, thereby revealing a promising target for adjunctive immunotherapy in severe COVID-19.

A persistent neutrophil-associated immune signature characterizes post–COVID-19 pulmonary sequelae

“…Effector mechanisms of neutrophils include formation of NETs that comprise networks of fibers composed of DNA containing histones and enzymes (myeloperoxidase and neutrophil elastase) (33). NET formation may have both protective and pathogenic roles; ample evidence indicates roles in propagation of inflammation in a range of conditions, including COVID-19 (34)(35)(36), and excessive NET formation can trigger a cascade leading to end-organ damage (37).…”

A persistent neutrophil-associated immune signature characterises post-COVID19 pulmonary sequelae

“…Effector mechanisms of neutrophils include formation of NETs which comprise networks of bres composed of DNA containing histones and enzymes including myeloperoxidase and neutrophil elastase 39 . NET formation may have protective and pathogenic roles; ample evidence indicates roles in initiation and propagation of in ammation in a range of clinical conditions including COVID19 [40][41][42] and excessive NET formation can trigger a cascade leading to tissue destruction and end-organ damage 43 .…”

“…IL-17C was also recently shown to be associated with disease progression in brosing interstial lung disease associated with connective tissue disease, chronic hypersensitivity pneumonitis or unclassi able origin 56 which further supports a broader role of this pathway in brogenesis. Notably, neutrophil priming and NET formation are poorly responsive to corticosteroids 42 which are now widely used for severe COVID19, emphasising that alternative approaches are needed. Future functional studies in mouse models of SARS-CoV2 (including a recently described humanised system that recapitulates disease features including pulmonary brosis 57 ) and/or longitudinal analysis of ongoing clinical trials examining effects of neutrophil targeting therapies such as elastase inhibitors (e.g.…”

Multi-omics Characterization of Neutrophil Extracellular Trap Formation in Severe and Mild COVID-19 Infections

“…Recent studies from SARS-CoV-2 patient neutrophils show elevated release of reactive oxygen species (44). Free radicals and oxidative stress pathways trigger NET formation.…”