The Emerging Role of Neutrophil Extracellular Traps in Severe Acute Respiratory Syndrome Coronavirus 2 (COVID-19)

Abstract

<jats:title>Abstract</jats:title> <jats:p>The novel coronavirus SARS-CoV2 causes COVID-19, a highly pathogenic viral infection threatening millions. The majority of those infected are asymptomatic or mildly symptomatic showing typical clinical signs of common cold. However approximately 20% of the patients can progress to acute respiratory distress syndrome (ARDS) and eventually death in about 5% of cases. Recently, angiotensin-converting enzyme 2 (ACE2) has been shown to be a functional receptor for virus entry into host target cells. The upregulation of ACE2 in patients with comorbidities may represent a propensity for increased viral load and spreading of infection to extrapulmonary tissues. This systemic infection is associated with higher neutrophil to lymphocyte ratio in infected tissues and high levels of pro-inflammatory cytokines leading to an extensive microthrombus formation with multiorgan failure. Herein we investigated whether SARS-CoV2 can stimulate extracellular neutrophils traps (NETs) in a process called NETosis. We demonstrated for the first time that SARS-CoV2 in fact is able to activate NETosis in human neutrophils. Our findings indicated that this process is associated with increased levels of intracellular Reactive Oxygen Species (ROS) in neutrophils. The ROS-NET pathway plays a role in thrombosis formation and our study suggest the importance of this target for therapy approaches against disease.</jats:p>

Longitudinal characterization of circulating neutrophils uncovers distinct phenotypes associated with disease severity in hospitalized COVID-19 patients

“…NETosis is implicated in severe COVID-19 pathology through transcriptomics, proteomics, and circulating cell-free DNA Several studies have reported associations between SARS-CoV-2 infection and NETs [47][48][49] . NETs are extracellular webs of chromatin that contain highly reactive oxidative enzymes such as myeloperoxidase which have the ability to capture and neutralize microbes including viruses 21 , but in excess can cause tissue damage and microvascular thrombosis 50 .…”

Hyperactive cytokine T-cell response is associated with immunosenescence in severe acute COVID-19 infection&nbsp;

“…In general, the predisposing factors for development of the cytokine storm consist of a diverse combination of mechanisms, involving viral escape associated with genetic defects of host defense, as well as other immunological abnormalities, such as high rate of neutrophil in ltration into target tissues. The infection and consequent activation of neutrophilic network and thrombocytogenesis lead to multiple organ failure (6,8). This mechanism of immunopathogenesis has been proposed as a determinant in the worsening of infection, contributing to the high morbidity and lethality seen in COVID-19 (1).…”

Infection and Immune Memory: Variables in Robust Protection by Vaccines Against SARS-CoV-2

“…Neutrophil responsive chemokine signature, secretion of NET (Neutrophil extra-cellular traps), and increased infiltration of neutrophils were found to be associated with severe cases of COVID-19 (29)(30)(31)(32).…”