Journal Article

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

Panda, Rachita, Shim, Hanjoo Brian, Yipp, Bryan G., McDonald, Braedon, Zucoloto, Amanda Z., Schlechte, Jared M., Kubes, Paul, Castanheira, Fernanda V.S., Surewaard, Bas G.J., Slavikova, Zdenka

2022

Overview

Acute respiratory distress syndrome (ARDS) is a life-threatening syndrome, constituted by 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, key outstanding questions are whether COVID-19 drives a unique program of neutrophil activation or effector functions that contribute 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 with those with 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. 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.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Adult / Aged / Aged, 80 and over / Alveoli / Cell activation / Clinical outcomes / COVID-19 / COVID-19 - immunology / COVID-19 - pathology / Cytotoxicity / Dexamethasone / Extracellular Traps - immunology / Female / Genotype & phenotype / Humans / Illnesses / Immune response / Immunology / Immunotherapy / Infections / Infectious disease / Leukocytes (neutrophilic) / Male / Middle Aged / Neutrophil Activation / Neutrophils / Neutrophils - immunology / Neutrophils - pathology / Pandemics / Pathogenesis / Pneumonia / Pneumonia, Bacterial - immunology / Pneumonia, Bacterial - pathology / Respiratory distress syndrome / Respiratory Distress Syndrome - immunology / Respiratory Distress Syndrome - pathology / Respiratory failure / SARS-CoV-2 - immunology / Severe acute respiratory syndrome coronavirus 2 / Severity of Illness Index / Ventilators