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

Publisher: BioMed Central Country of Publication: England NLM ID: 101190741 Publication Model: Electronic Cited Medium: Internet ISSN: 1479-5876 (Electronic) Linking ISSN: 14795876 NLM ISO Abbreviation: J Transl Med Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2003-

Extracellular Traps*/metabolism ; COVID-19* ; Nervous System Diseases*; Humans ; Neutrophils/metabolism ; Deoxyribonucleases/metabolism ; Deoxyribonuclease I/metabolism ; Inflammation/metabolism

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).
(© 2024. The Author(s).)

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ANR grant RA-COVID-19 Agence Nationale de la Recherche

ClinicalTrials.gov NCT04332016; NCT04356495

EC 3.1.- (Deoxyribonucleases)
EC 3.1.21.1 (Deoxyribonuclease I)

Date Created: 20240308 Date Completed: 20240311 Latest Revision: 20240807

20240807

PMC10919029

10.1186/s12967-024-05044-7

38454482