Neutrophil Extracellular Traps in COVID-19: A Double Edge Sword

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Authors: Sehrish Gohar Ali, Dr. Rizwan Alam

Department of Biochemistry, Quaid-i-Azam University Islamabad, 45320, Pakistan.

As of September 2020, more than 30 million confirmed cases of Covid-19 and about 9 million deaths have been documented worldwide. The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has emerged as a global challenge for the scientists and clinicians due to increasingly complex clinical features that are not only difficult to manage but are potentially fatal. The hyperactivation of patients’ immune system, often termed as a cytokine storm, is often reported to be one of the reasons behind mortality in many cases.

Neutrophils, a vital component of our immune system, play a fundamental role in the fight against a variety of pathogens by their complex weaponry including the formation of neutrophil extracellular traps (NETs). In the early phase of the pandemic, many immunologists working on NETs directed their focus to their role in the development of Covid-19.

What are NETs?

NETs are extrusions of protein-bound DNA that are released from the neutrophils in response to a plethora of biochemical signals arising from infectious agents or the host’s own immune system. These intricate complexes of proteins and DNA are utilized to trap and kill the invading pathogens including bacteria and viruses as an essential part of the innate immune response.

However, uncontrolled production or attenuated clearance of NETs can damage our own body by instigating the auto-immune responses. Specifically, the virus-induced NETs are known to circulate in the blood and stimulate pro-inflammatory responses such as the production of chemokines, cytokines, and other immune mediators.

How do NETs contribute to the development of Covid-19?

The presence of neutrophil infiltrate at the infection sites is well documented in other pandemic viruses of the same coronavirus family including SARS-CoV and MERS-CoV. Therefore, the association of neutrophils and NETs in the pathogenicity of Covid-19 was highly suspected. Not surprisingly, as the pandemic continues, emerging evidence is indicating the presence of NETs as a crime partner of SARS-CoV-2 in many reported mild, moderate, and severe cases of Covid-19. In April 2020, a team of scientists from the United States was the first to report the presence of intense infiltration of neutrophils in the alveoli and pulmonary interstitial spaces of Covid-19 patients. Based on their observations of lung histology, they proposed a potential role of NETs in severe cases of Covid-19. Later, studies involving Covid-19 patients in Italy, Germany, Switzerland, and the United States observed the presence of intra-alveolar neutrophils as a prominent feature of Covid-19.

Moreover, the higher numbers of circulating neutrophils observed in Covid-19 patients clearly indicate the contribution of neutrophils to the pathogenesis and severity of the disease. Several pathological conditions showing excessive NETs formation in Covid-19 patients have been reported including:

  • Respiratory failure
  • ARDS
  • Acute cardiac injury/heart failure
  • Kidney diseases
  • Gouty arthritis sensitization
  • Vasculitis
  • Chronic inflammatory diseases
  • Inflammatory bowel disease
  • Sepsis
  • Rheumatoid arthritis
  • Neuropathy
  • Type 1 diabetes sensitization

Up till now, studies have highlighted the NETs-associated amplifier loop involving hyper inflammation due to cytokines storm in severe clinical presentations of Covid-19 such as acute respiratory distress syndrome (ARDS), micro-vascular injury, thrombotic complications, and acute multi-organ dysfunction/failure. Interestingly, recent findings from Covid-19 patients have linked disproportionate NETs formation with high levels of interferons, other pro-inflammatory cytokines, and elevated presence of fibrin and its degradation product (D-dimer). These NETs-associated biological outcomes in severe Covid-19 patients are speculated to be the culprit in severe NETopathies along with other vascular complications. Nevertheless, most of these studies were launched valiantly and in urgency under unanticipated and challenging conditions. Therefore, the NETs-mediated Covid-19 disease severity and associated pathophysiological features require the execution of more systematic studies at a larger scale.

Can NETs be a drug target in Covid-19?

To reduce the NETs-induced hyper-inflammation in Covid-19, steroids such as dexamethasone and NSAIDs (non-steroidal anti-inflammatory drugs) including aspirin, have been employed as the first attempt in several clinical trials. Intriguingly, besides its anti-inflammatory role, aspirin also acts as an anticoagulant for NETs-induced immunothrombotic events and thus is of interest in the relevant ongoing clinical trials. Although the evidence for NETs as the crime partners of SARS-CoV-2 is growing, the data is still not enough as compared to the rate of spread, lethality, and novelty of the Covid-19 pandemic. Thus, it is the time to take NETs seriously in the context of the Covid-19 pandemic with a requirement to investigate the NETs inhibitors for the development of effective clinical interventions.

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