Abstract
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.
Highlights
Acute respiratory distress syndrome (ARDS) is a life-threatening syndrome of hypoxemic respiratory failure and diffuse alveolar damage that results from an aberrant host response to respiratory and systemic insults, with the most common cause being severe pneumonia [1]
It is well established that SARS-CoV-2 induces a unique systemic immune response that is central to the pathogenesis of severe COVID-19, including a putative role for neutrophils in the progression of disease during SARS-CoV-2 infection
To systematically examine the contribution of neutrophils to systemic immune dysregulation in severe COVID-19, we investigated the cellular immune landscape in the bloodstream of patients with ARDS caused by COVID-19 pneumonia or bacterial pneumonia
Summary
Acute respiratory distress syndrome (ARDS) is a life-threatening syndrome of hypoxemic respiratory failure and diffuse alveolar damage that results from an aberrant host response to respiratory and systemic insults, with the most common cause being severe pneumonia [1]. SARS-CoV-2 infection has emerged as the dominant cause of ARDS worldwide in the context of the COVID-19 pandemic [3] This has created an explosion of research to understand why SARSCoV-2 infection is so prone to causing ARDS, and much has been learned about the pathogenesis including aberrant local and systemic immune responses elicited by the virus. Neutrophils within the pulmonary microvasculature of severe COVID-19 are associated with widespread neutrophil extracellular trap (NETs) production [11,12,13,14] This dysregulated neutrophil effector response is thought to contribute to impaired gas exchange through the induction of microvascular thrombosis and perfusion defects, as well as tissue injury and diffuse alveolar damage
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