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

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...

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Bibliographic Details
Published in:JCI insight 2022-01, Vol.7 (2)
Main Authors: Panda, Rachita, Castanheira, Fernanda Vs, Schlechte, Jared M, Surewaard, Bas Gj, Shim, Hanjoo Brian, Zucoloto, Amanda Z, Slavikova, Zdenka, Yipp, Bryan G, Kubes, Paul, McDonald, Braedon
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
COVID-19 - immunology
COVID-19 - pathology
Extracellular Traps - immunology
Female
Humans
Immunology
Infectious disease
Male
Middle Aged
Neutrophil Activation
Neutrophils - immunology
Neutrophils - pathology
Pneumonia, Bacterial - immunology
Pneumonia, Bacterial - pathology
Respiratory Distress Syndrome - immunology
Respiratory Distress Syndrome - pathology
SARS-CoV-2 - immunology
Severity of Illness Index
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Summary: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.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.152291