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

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...

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Vydané v:Journal of translational medicine Ročník 22; číslo 1; s. 246 - 18
Hlavní autori: Garcia, Geoffrey, Labrouche-Colomer, Sylvie, Duvignaud, Alexandre, Clequin, Etienne, Dussiau, Charles, Trégouët, David-Alexandre, Malvy, Denis, Prevel, Renaud, Zouine, Atika, Pellegrin, Isabelle, Goret, Julien, Mamani-Matsuda, Maria, Dewitte, Antoine, James, Chloe
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: London BioMed Central 07.03.2024
BioMed Central Ltd
Springer Nature B.V
BMC
Predmet:
Adaptive immunology
Analysis
Antigens
Biomarkers
Biomedical and Life Sciences
Biomedicine
Care and treatment
Clinical deterioration
COVID-19
Cytotoxicity
Dendritic cells
Deoxyribonuclease
Emerging diseases
Hospital patients
Hospitalization
Human health and pathology
Immunology
ImmunoVirology and ImmunoOncology
Infectious diseases
Inflammation
Innate immunity
Intensive care
Leukocytes (neutrophilic)
Life Sciences
Lymphocytes
Medicine/Public Health
Neutrophils
Pandemics
Patients
Physiology
Proteins
Ratios
RNA sequencing
Sepsis
Testing
France
ISSN:1479-5876, 1479-5876
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Shrnutí: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
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ISSN:1479-5876
1479-5876
DOI:10.1186/s12967-024-05044-7