Impaired balance between neutrophil extracellular trap formation and degradation by DNases in COVID-19 disease

Abstract

Background Thrombo-inflammation and neutrophil extracellular traps (NETs) are exacerbated in severe cases of COVID-19, potentially contributing to disease exacerbation. However, the mechanisms underpinning this dysregulation remain elusive. We hypothesised that lower DNase activity may be associated with higher NETosis and clinical worsening in patients with COVID-19. Methods Biological samples were obtained from hospitalized patients (15 severe, 37 critical at sampling) and 93 non-severe ambulatory cases. Our aims were to compare NET biomarkers, functional DNase levels, and explore mechanisms driving any imbalance concerning disease severity. Results Functional DNase levels were diminished in the most severe patients, paralleling an imbalance between NET markers and DNase activity. DNase1 antigen levels were higher in ambulatory cases but lower in severe patients. DNase1L3 antigen levels remained consistent across subgroups, not rising alongside NET markers. DNASE1 polymorphisms correlated with reduced DNase1 antigen levels. Moreover, a quantitative deficiency in plasmacytoid dendritic cells (pDCs), which primarily express DNase1L3, was observed in critical patients. Analysis of public single-cell RNAseq data revealed reduced DNase1L3 expression in pDCs from severe COVID-19 patient. Conclusion Severe and critical COVID-19 cases exhibited an imbalance between NET and DNase functional activity and quantity. Early identification of NETosis imbalance could guide targeted therapies against thrombo-inflammation in COVID-19-related sepsis, such as DNase administration, to avert clinical deterioration. Trial registration: COVERAGE trial (NCT04356495) and COLCOV19-BX study (NCT04332016). Graphical Abstract

Post‐COVID pulmonary injury in K18‐hACE2 mice shows persistent neutrophils and neutrophil extracellular trap formation

“…While de Diego and colleagues reported that only cell‐free DNA in the plasma but not other NET markers correlated with disease severity, 12 other studies have shown the association of multiple markers of NET with severe COVID‐19. 4 , 13 , 14 Our recent study also indicates that mature neutrophils with heightened activation phenotype remained in circulation for up to 6 months in PASC patients with persistent pulmonary sequelae. 15 Therefore, it is essential to identify clinically relevant NET markers that are highly associated with post‐COVID pulmonary fibrosis and test them as therapeutic targets.…”