Abstract
The severity of coronavirus disease 19 (COVID-19) is associated with neutrophil extracellular trap (NET) formation. During NET formation, cytotoxic extracellular histones are released, the presence of which is linked to the initiation and progression of several acute inflammatory diseases. Here we study the presence and evolution of extracellular histone H3 and several other neutrophil-related molecules and damage-associated molecular patterns (DAMPs) in the plasma of 117 COVID-19-positive ICU patients. We demonstrate that at ICU admission the levels of histone H3, MPO, and DNA-MPO complex were all significantly increased in COVID-19-positive patients compared to control samples. Furthermore, in a subset of 54 patients, the levels of each marker remained increased after 4+ days compared to admission. Histone H3 was found in 28% of the patients on admission to the ICU and in 50% of the patients during their stay at the ICU. Notably, in 47% of histone-positive patients, we observed proteolysis of histone in their plasma. The overall presence of histone H3 during ICU stay was associated with thromboembolic events and secondary infection, and non-cleaved histone H3 was associated with the need for vasoactive treatment, invasive ventilation, and the development of acute kidney injury. Our data support the validity of treatments that aim to reduce NET formation and additionally underscore that more targeted therapies focused on the neutralization of histones should be considered as treatment options for severe COVID-19 patients.
Highlights
The global pandemic of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) has infected over 120 million people and caused 2.5 million deaths as of March 2021 to the associated coronavirus disease 19 (COVID-19) (WHO, 2021)
Extracellular histones act as damage-associated molecular patterns (DAMPs) that contribute to the immune response by promoting immune cell activation, inflammasome formation, and proinflammatory cytokine release
The presence of the individual neutrophil extracellular trap (NET)-related markers histone H3, cell-free DNA (cfDNA), neutrophil elastase (NE), MPO, and MPO-DNA complexes was assessed in citrated plasma of 117 SARS-COV-2 positive patients admitted to the ICU at Uppsala University Hospital, Sweden
Summary
The global pandemic of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) has infected over 120 million people and caused 2.5 million deaths as of March 2021 to the associated coronavirus disease 19 (COVID-19) (WHO, 2021). As the SARS-CoV-2 viral infection activates neutrophils to form NETs (Busch et al, 2020; Veras et al, 2020), their intracellular components are released into the extracellular space. These intracellular components include cell-free DNA (cfDNA), histones, and granules containing neutrophil elastase (NE) and myeloperoxidase (MPO) (Brinkmann et al, 2004). The release of histones during NET formation or after cell death facilitates the histonemediated neutralization of pathogens (Silvestre-Roig et al, 2019). Extracellular histones act as damage-associated molecular patterns (DAMPs) that contribute to the immune response by promoting immune cell activation, inflammasome formation, and proinflammatory cytokine release. Extracellular histones are able to damage a range of host cells (Xu et al, 2009; Abrams et al, 2013; Cheng et al, 2019), and neutralization of extracellular histones by either complexation (Wildhagen et al, 2014; Silvestre-Roig et al, 2019; Schumski et al, 2021) or proteolytic cleavage (Chen et al, 2014) was shown to be beneficial in reducing the degree of tissue and organ damage
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