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.

COVID‐19 immunopathology: From acute diseases to chronic sequelae

“… 108 Recently, it was shown that neutrophils from COVID‐19 patients with ARDS are primed to form NETs as compared to COVID‐19 with non‐ARDS. 109 Furthermore, neutrophils isolated from COVID‐19 patients are more susceptible to release NETs as compared to healthy donors. 108 , 109 In a different study, sera of COVID‐19 patients were demonstrated to have an increased level of myeloperoxidase DNA and citrullinated histone H3, markers for NET.…”

“… 109 Furthermore, neutrophils isolated from COVID‐19 patients are more susceptible to release NETs as compared to healthy donors. 108 , 109 In a different study, sera of COVID‐19 patients were demonstrated to have an increased level of myeloperoxidase DNA and citrullinated histone H3, markers for NET. 110 Additionally, serum from these COVID‐19 patients was able to induce NET formation in healthy neutrophils, indicating that both serum and intrinsic factors in neutrophils can govern NET formation.…”

Dichotomous Role of Tumor Necrosis Factor in Pulmonary Barrier Function and Alveolar Fluid Clearance

“…COVID-19 endothelialitis is associated with platelet aggregation and thrombocoagulatory and fibrinolysis-inhibitory ( D’Agnillo et al, 2021 ) features that can obstruct vessels, as manifested by the important frequency of thromboses, including pulmonary thromboembolism. This has been shown particularly in the pulmonary microvasculature, especially in vessels with a cross-sectional area between 1.25 and 5 mm 2 ( Libby and Lüscher, 2020 ; Morris et al, 2021 ), containing highly activated and functionally distinct neutrophils, which generate neutrophil extracellular traps (NETs) ( Leppkes et al, 2020 ; Zuo et al, 2020 ; Panda et al, 2021 ), which may stimulate alternative treatment strategies besides corticosteroids and standard care ( Panda et al, 2021 ). One has to question whether virus-associated endothelial cell injury, quite frequently co-localized with NETs, or rather the collateral of other inflammatory processes in plasma, represents the key step to neutrophil activation.…”

Immune Cell Plasticity in Inflammation: Insights into Description and Regulation of Immune Cell Phenotypes

“…This work highlights distinct neutrophil phenotypes, identifying a functional priming towards NET release without alteration of other cellular functions, such as ROS production. This phenotype existed independently of dexamethasone treatment, highlighting the necessity of other more accurate therapeutics targeting discrete neutrophil functional phenotypes [ 288 ]. Therapeutic consequences of these phenotypic pathway assessments are so far limited but might aid in the differentiation of patient subcategories and sooner or later the targeted intervention with regard to pro-/anti-inflammatory cell populations.…”