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Neutrophil Extracellular Traps and COVID-19 Severity

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A group of eleven international medical research organizations is investigating the role that neutrophil extracellular traps (NETs) may play in the development and severity of COVID-19. The NETwork consortium recently published a paper outlining their hypothesis that overactive neutrophils could be responsible for the severe symptoms seen in some COVID-19 patients.

Technology Networks
 spoke with Betsy Barnes, Professor at the Feinstein Institutes for Medical Research, and lead author of the paper, to learn more about NETs, the ways they might contribute to the clinical characteristics of COVID-19, and how they could serve as a therapeutic target. 

Anna MacDonald (AM): Can you tell us about the NETwork’s aims and what spurred its formation?

Betsy Barnes (BB):
 The main aim of the NETwork is to create a collaborative framework to advance research that will have an impact on the understanding, diagnosis, prevention or treatment of COVID-19. The NETwork consists of clinicians and researchers that have studied neutrophils and NETs in the context of other diseases, and who came together with a common belief that NETs were contributing to the severity of COVID-19. 

What is the normal role of neutrophils in the lungs? 

 In brief, the normal role of neutrophils in the lungs (and elsewhere in the body) is to kill pathogens and remove cellular debris.

Laura Lansdowne (LL): What are neutrophil extracellular traps (NETs)? 

 NETs are made up of DNA, histones and granular enzymes that are expelled from neutrophils to trap and kill pathogens.

AM: What leads to their production?

 When neutrophils become activated in response to pathogens, they can form NETs. Neutrophils can also be stimulated by cytokines, such as interleukin 1 beta (IL-1β) and IL-8, to form NETs. 

 What is the result of excessive NET formation?

 Although NETs are beneficial in the host defense against pathogens, collateral damage from sustained NET formation can stimulate a variety of disease processes. As related to COVID-19, excessive NET formation can trigger a cascade of inflammatory reactions that destroy surrounding tissues, cause microthrombosis, and result in permanent organ damage to the lung, heart and kidneys. 

LL: Can you elaborate on the parallels you have been able to draw from other NET-driven diseases in terms of clinical presentation, and touch on how these findings support your theory that NETs might feature in COVID-19?

 Patients with severe COVID-19 have increased lung inflammation, thick mucus secretions in the lung airways, elevated serum cytokine levels, extensive lung damage, and microthrombosis. Many of these characteristics are similar to that seen in patients with diseases such as acute respiratory distress syndrome (ARDS), severe coronary artery disease and cystic fibrosis. And, a variety of drugs that lead to the inhibition of NETs have been used to treat these diseases, supporting our theory that NETs might contribute to the clinical characteristics of COVID-19.

AM: Are some people more prone to producing NETs than others?

 This is an excellent question and we do not know for certain; however, a recent study by my lab suggested that genetics may contribute to a microenvironment that makes neutrophils more prone to producing NETs. This particular study was in the context of factors that drive the autoimmune disease systemic lupus erythematous (SLE).  

AM: How are levels of NETs detected in patients? 

 The easiest way to detect NETs in patients is by a plasma ELISA. It can also be done on neutrophils isolated from patient blood.

LL: If you do discover that excess NETs cause the severe symptoms of COVID-19, how will this impact the therapeutic strategies that may be deployed to help patients with the disease?

 There are drugs currently available that inhibit NETs. Some are already used to treat patients with other diseases, as mentioned above, and others are in different stages of clinical development. One of the primary goals of the NETwork is to accelerate the validation of off-label treatments and pre-approved drugs for clinical trials to support patients with COVID-19.

Betsy Barnes was speaking to Anna MacDonald and Laura Elizabeth Lansdowne, Science Writers, Technology Networks.