Proteomics identifies a type I IFN, prothrombotic hyperinflammatory circulating COVID-19 neutrophil signature distinct from non-COVID-19 ARDS

Reyes, L.; Sanchez-Garcia, M. A.; Morrison, T.; Howden, A. J.; Watts, E. R.; Arienti, S.; Sadiku, P.; Coelho, P.; Mirchandani, A. S.; Hope, D.; Clark, S. K.; Singleton, J.; Johnston, S.; Grecian, R.; Poon, A.; McNamara, S.; Harper, I.; Fourman, M. H.; Brenes, A. J.; Pathak, S.; Lloyd, A.; Rodriguez Blanco, G.; Von Kriegsheim, A.; Ghesquiere, B.; Vermaelen, W.; Cologna, C. T.; Dhaliwal, K.; Hirani, N.; Dockrell, D.; Whyte, M. K.; Griffith, D. M.; Cantrell, D. A.; Walmsley, S. R.

Understanding the mechanisms by which infection with SARS-CoV-2 leads to acute respiratory distress syndrome (ARDS) is of significant clinical interest given the mortality associated with severe and critical coronavirus induced disease 2019 (COVID-19). Neutrophils play a key role in the lung injury characteristic of non-COVID-19 ARDS, but a relative paucity of these cells is observed at post-mortem in lung tissue of patients who succumb to infection with SARS-CoV-2. With emerging evidence of a dysregulated innate immune response in COVID-19, we undertook a functional proteomic survey of circulating neutrophil populations, comparing patients with COVID-19 ARDS, non-COVID-19 ARDS, moderate COVID-19, and healthy controls. We observe that expansion of the circulating neutrophil compartment and the presence of activated low and normal density mature and immature neutrophil populations occurs in both COVID-19 and non-COVID-19 ARDS. In contrast, release of neutrophil granule proteins, neutrophil activation of the clotting cascade and formation of neutrophil platelet aggregates is significantly increased in COVID-19 ARDS. Importantly, activation of components of the neutrophil type I IFN responses is specific to infection with SARS-CoV-2 and linked to metabolic rewiring. Together this work highlights how differential activation of circulating neutrophil populations may contribute to the pathogenesis of ARDS, identifying processes that are specific to COVID-19 ARDS.