NETs By-products and Extracellular DNA May Play a Key Role in COVID-19 Pathogenesis: Incidence on Patient Monitoring and Therapy

Abstract

Neutrophils play an important role as the first line of innate immune defense. One function of neutrophils, called neutrophil extracellular traps (NETs), has been discovered recently. NETs are extensive fibrous structures released extracellularly from activated neutrophils in response to infection. They are composed of cytosolic protein assembled on a scaffold of released chromatin. These structures suppress the dissemination of micro-organisms in blood by trapping them mechanically, and by exploiting coagulant function to segregate them within the circulation. In addition, NET components (DNA, histone, and granule proteins) also contribute to the triggering of an inflammatory process. NET function, however, can be regarded as a double-edged sword. On one hand, NET formation is an efficient strategy for neutralizing invading micro-organisms. On the other hand, NET can be harmful to the host, as its exposed by-products that are toxic to endothelial cells and parenchymal tissue. We present here the analogous biological and physiological features of the harmful positive amplification loop between inflammation and tissue damage induced by NETosis dysregulation and Coronavirus Disease-2019 (COVID-19) pathogenesis. Considering the rapid evolution of this disease symptoms and its lethality, we hypothesize that COVID-19 progresses under an amplifier loop, leading to an massive, uncontrolled inflammation process. We also describe the correlations of COVID-19 symptoms and biological features with those consecutive to uncontrolled NET formation causing various sterile or infectious diseases. General clinical conditions, and numerous pathological and biological features, are analogous with NETs deleterious effects. We postulate that Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV2) induces a disproportionate virus-induced NET release, and that this plays a key role in COVID-19 pathogenesis. While neutrophils are the principal starting point for extracellular and circulating DNA release, targeting NETs rather than neutrophils themselves may stand for an effective strategy. This paper offers an in-depth review of NET formation, function and pathogenic dysregulation, as well as of current and future therapies to control NET unbalance. As such, it enables us also to suggest new therapeutic strategies to fight COVID-19. In combination with or independent of the latest tested approaches, we propose that, in the short term, deoxyribonuclease I (DNase-1) treatment should be evaluated; we also advocate a significant increase in research on the development of toll-like receptors (TLR) and C-type Lectin like receptors (CLEC) inhibitors, and on anti-IL26 therapies.Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 15 April 2020

Comprehensive Transcriptomic Analysis of COVID-19 Blood, Lung, and Airway

“…The lung tissue was enriched in gene signatures of Mo/MΦs as well as other myeloid cells including neutrophils and LDGs. The role of neutrophils and LDGs in COVID-19 pathogenesis has been poorly characterized, although increases in blood neutrophils have been found to be associated with poor disease outcome in COVID-19 patients and some have proposed that the formation of neutrophil extracellular traps (NETs) contributes to increased risk of death from SARS-CoV2 infection (Barnes et al, 2020;Huang et al, 2020;Thierry and Roch, 2020). Although LDGs have not been previously reported in the COVID-19 lung, in comparison to neutrophils, they exhibit an enhanced capacity to produce Type I IFNs and form NETs and therefore, may have an even greater impact on disease progression (Carmona-Rivera and Kaplan, 2013).…”

Non‐steroidal anti‐inflammatory drugs, prostaglandins, and COVID‐19

“…milieu (Barnes et al, 2020;Mozzini & Girelli, 2020;Thierry, 2020;Thierry & Roch, 2020;Tomar, Anders, Desai, & Mulay, 2020). Indeed, there is a high degree of NET-IL-1β interplay during both venous and arterial thrombosis and severe asthma (Lachowicz-Scroggins et al, 2019;Liberale et al, 2019;Yadav et al, 2019), and it has been hypothesised that there may be therapeutic potential in targeting the IL-1β/NET feedback loop (Yaqinuddin & Kashir, 2020).…”

Anti-protease Treatments Targeting Plasmin(ogen) and Neutrophil Elastase May Be Beneficial in Fighting COVID-19

“…We recently proposed a novel hypothesis (10) concerning COVID-19 pathogenesis which is linked to that of Ji et al (6). We are convinced that neutrophil extracellular traps (NETs) formation and its byproducts play a key role in COVID-19 pathogenesis (10). NETs are extensive structures released extracellularly from activated neutrophils in response to infection.…”

“…NETs are extensive structures released extracellularly from activated neutrophils in response to infection. They are composed of cytosolic protein assembled on a scaffold of released chromatin (10). These structures prevent the dissemination of microorganisms in blood by trapping them mechanically and by exploiting the coagulant function to segregate them within the circulation (5).…”

“…In addition to this, NET components [DNA, histone, and granule proteins such as myeloperoxidase and elastase (NE)] also contribute to the triggering of an inflammatory process. The dysregulation of NET formation and the consecutive release of NET byproducts is involved in thrombosis and fibrinolysis disorders in autoimmune diseases, as well as non-autoimmune diseases, in particular viral infection (1,5,10).…”