The role of extracellular histones in COVID-19

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread from China within 2 months to become a global pandemic. Infection can cause a diversity of symptoms ranging from asymptomatic to severe acute respiratory distress syndrome (ARDS) with an increased risk of vascular hyperpermeability, pulmonary inflammation, extensive lung damage and thrombosis. One of the host defense systems in coronavirus disease 2019 (COVID-19) is the formation of neutrophil extracellular traps (NETs). Numerous studies have revealed elevated levels of NET components, such as cell-free DNA (cfDNA), extracellular histones, neutrophil elastase (NE) and myeloperoxidase (MPO), in plasma, serum and tracheal aspirates of severe COVID-19 patients. Extracellular histones, a major component of NETs, are clinically very relevant since they represent promising biomarkers and drug targets given that several studies have identified histones as key mediators in the onset and progression of various diseases, including COVID-19. However, the role of extracellular histones in COVID-19 per se remains relatively under-explored. Histones are nuclear proteins that can be released into the extracellular space via apoptosis, necrosis or NET formation and are then regarded as cytotoxic damage-associated molecular patterns (DAMPs) that have the potential to damage tissues and impair organ function. This review will highlight the mechanisms of extracellular histone-mediated cytotoxicity and focus on the role that histones play in COVID-19. Thereby this paper facilitates a bench-to-bedside view of extracellular histone-mediated cytotoxicity, its role in COVID-19, and histones as potential drug targets and biomarkers for future theranostics in the clinical treatment of COVID-19 patients. This article is protected by copyright. All rights reserved.