Impaired Degradation of Neutrophil Extracellular Traps: A Possible Severity Factor of Elderly Male COVID-19 Patients

Neutrophil extracellular traps (NETs) have been described as a potential trigger of severe COVID-19. NETs are known as extracellular DNA fibers released by neutrophils in response to infection. If the host is unable to balance efficient clearance of NETs by dornases (DNases), detrimental consequences occur. Elevated levels of NETs in COVID-19 patients are associated with higher risk of morbid thrombotic complications. Here, we studied the level of NET markers and DNase activity in a cohort of COVID-19 patients compared to healthy controls. Our data confirmed an increased level of NET markers in the plasma of COVID-19 patients, with a higher level in male compared to female patients. At the same time, there was an increased DNase activity detectable in COVID-19 patients compared to healthy controls. Importantly, there was a negative correlation of DNase activity with the age of male patients. The antimicrobial peptide LL-37, which is known to stabilize NETs against DNase degradation, is embedded in NETs upon severe acute respiratory syndrome coronavirus-2-infection. The LL-37 plasma level correlates with the NET-marker level in male COVID-19 patients, indicating a potential role of LL-37 in the risk of NET-associated thrombosis in male COVID-19 patients by stabilizing NETs against DNase degradation. In conclusion, our data identify two potential risk factors of elderly male patients which may lead to inefficient NET degradation and a subsequently higher risk of NET-associated thrombosis during COVID-19: reduced DNase activity and an increased LL-37 level.

[1]  Santosh K. Ghosh,et al.  Ramping Up Antimicrobial Peptides Against Severe Acute Respiratory Syndrome Coronavirus-2 , 2021, Frontiers in Molecular Biosciences.

[2]  R. Cavallazzi,et al.  A specific low-density neutrophil population correlates with hypercoagulation and disease severity in hospitalized COVID-19 patients , 2021, JCI insight.

[3]  M. Gates,et al.  Risk factors for severity of COVID-19: a rapid review to inform vaccine prioritisation in Canada , 2021, BMJ Open.

[4]  W. Baumgärtner,et al.  Vasculitis and Neutrophil Extracellular Traps in Lungs of Golden Syrian Hamsters With SARS-CoV-2 , 2021, Frontiers in Immunology.

[5]  J. Schultze,et al.  Neutrophils in COVID-19 , 2021, Frontiers in Immunology.

[6]  E. Cavalier,et al.  Circulating Nucleosomes as Potential Markers to Monitor COVID-19 Disease Progression , 2021, Frontiers in Molecular Biosciences.

[7]  M. von Köckritz-Blickwede,et al.  The Balance of Neutrophil Extracellular Trap Formation and Nuclease Degradation: an Unknown Role of Bacterial Coinfections in COVID-19 Patients? , 2021, mBio.

[8]  S. Mallapaty.  What's the risk of dying from a fast-spreading COVID-19 variant? , 2021, Nature.

[9]  N. Mackman,et al.  Circulating Markers of Neutrophil Extracellular Traps Are of Prognostic Value in Patients With COVID-19 , 2020, Arteriosclerosis, thrombosis, and vascular biology.

[10]  Jiangguo Lin,et al.  Insights Into Immunothrombosis: The Interplay Among Neutrophil Extracellular Trap, von Willebrand Factor, and ADAMTS13 , 2020, Frontiers in Immunology.

[11]  P. Saldiva,et al.  SARS-CoV-2–triggered neutrophil extracellular traps mediate COVID-19 pathology , 2020, The Journal of experimental medicine.

[12]  C. Albanesi,et al.  Immunomodulatory Role of the Antimicrobial LL-37 Peptide in Autoimmune Diseases and Viral Infections , 2020, Vaccines.

[13]  Alexander Sczyrba,et al.  Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment , 2020, Cell.

[14]  M. Neurath,et al.  Vascular occlusion by neutrophil extracellular traps in COVID-19 , 2020, EBioMedicine.

[15]  C. Schwerk,et al.  Role of Bacterial and Host DNases on Host-Pathogen Interaction during Streptococcus suis Meningitis , 2020, International journal of molecular sciences.

[16]  N. Mackman,et al.  Coagulation Abnormalities and Thrombosis in Patients Infected With SARS-CoV-2 and Other Pandemic Viruses , 2020, Arteriosclerosis, thrombosis, and vascular biology.

[17]  Konrad U. Förstner,et al.  Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients , 2020, Genome Medicine.

[18]  C. Takiya,et al.  The emerging role of neutrophil extracellular traps in severe acute respiratory syndrome coronavirus 2 (COVID-19) , 2020, Scientific Reports.

[19]  Robert A. Campbell,et al.  Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome , 2020, Blood.

[20]  J. Desilles,et al.  Efficacy and safety of aerosolized intra-tracheal dornase alfa administration in patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS): a structured summary of a study protocol for a randomised controlled trial , 2020, Trials.

[21]  G. De Pergola,et al.  Worse progression of COVID‐19 in men: Is testosterone a key factor? , 2020, Andrology.

[22]  Hongyue Li,et al.  Preliminary evaluation of the safety and efficacy of oral human antimicrobial peptide LL-37 in the treatment of patients of COVID-19, a small-scale, single-arm, exploratory safety study , 2020, medRxiv.

[23]  E. Ovalı,et al.  Preliminary report of in vitro and in vivo effectiveness of dornase alfa on SARS-CoV-2 infection , 2020, New Microbes and New Infections.

[24]  R. Woods,et al.  Neutrophil extracellular traps in COVID-19. , 2020, JCI insight.

[25]  M. von Köckritz-Blickwede,et al.  Detection, Visualization, and Quantification of Neutrophil Extracellular Traps (NETs) and NET Markers. , 2020, Methods in molecular biology.

[26]  M. Hoffmann,et al.  The double-edged role of neutrophil extracellular traps in inflammation. , 2019, Biochemical Society transactions.

[27]  Rabea Imker,et al.  From Stable to Lab—Investigating Key Factors for Sudden Deaths Caused by Streptococcus suis , 2019, Pathogens.

[28]  K. Waldmann,et al.  Degraded neutrophil extracellular traps promote the growth of Actinobacillus pleuropneumoniae , 2019, Cell Death & Disease.

[29]  M. Ahn,et al.  Circulating DNAs, a Marker of Neutrophil Extracellular Traposis and Cancer-Related Stroke. , 2019, Stroke.

[30]  Abel J Bronkhorst,et al.  The diverse origins of circulating cell‐free DNA in the human body: a critical re‐evaluation of the literature , 2018, Biological reviews of the Cambridge Philosophical Society.

[31]  T. Renné,et al.  Host DNases prevent vascular occlusion by neutrophil extracellular traps , 2017, Science.

[32]  J. Tembl,et al.  Neutrophil extracellular traps are increased in patients with acute ischemic stroke: prognostic significance , 2017, Thrombosis and Haemostasis.

[33]  S. Yuan,et al.  Neutrophil‐mediated vascular barrier injury: Role of neutrophil extracellular traps , 2017, Microcirculation.

[34]  A. Tsung,et al.  Neutrophil extracellular traps are indirectly triggered by lipopolysaccharide and contribute to acute lung injury , 2016, Scientific Reports.

[35]  Irma E. Gonzalez-Curiel,et al.  Evidence of sexual dimorphism in placental vitamin D metabolism: Testosterone inhibits calcitriol-dependent cathelicidin expression , 2016, The Journal of Steroid Biochemistry and Molecular Biology.

[36]  V. Nizet,et al.  Novel Role of the Antimicrobial Peptide LL-37 in the Protection of Neutrophil Extracellular Traps against Degradation by Bacterial Nucleases , 2014, Journal of Innate Immunity.

[37]  T. Harrer,et al.  Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines , 2014, Nature Medicine.

[38]  J. van der Vlag,et al.  Breaking Immunological Tolerance in Systemic Lupus Erythematosus , 2014, Front. Immunol..

[39]  G. Menexes,et al.  Salivary concentration of the antimicrobial peptide LL-37 in patients with oral lichen planus , 2014, Journal of oral microbiology.

[40]  S. Gandhi,et al.  Ocular surface extracellular DNA and nuclease activity imbalance: a new paradigm for inflammation in dry eye disease. , 2012, Investigative ophthalmology & visual science.

[41]  Abdul Hakkim,et al.  Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps , 2010, The Journal of cell biology.

[42]  J. Hartwig,et al.  Extracellular DNA traps promote thrombosis , 2010, Proceedings of the National Academy of Sciences.

[43]  Abdul Hakkim,et al.  Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis , 2010, Proceedings of the National Academy of Sciences.

[44]  R. Swaminathan,et al.  Overview of Circulating Nucleic Acids in Plasma/Serum , 2008, Annals of the New York Academy of Sciences.

[45]  Stephen R. Clark,et al.  Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood , 2007, Nature Medicine.

[46]  V. Wahn,et al.  Novel cell death program leads to neutrophil extracellular traps. , 2007, The Journal of cell biology.

[47]  A. Zychlinsky,et al.  Neutrophil Extracellular Traps Kill Bacteria , 2004, Science.

[48]  Domenico Romeo,et al.  Cathelicidins: a novel protein family with a common proregion and a variable C‐terminal antimicrobial domain , 1995, FEBS letters.