Novel therapeutic targets for SARS-CoV-2-induced acute lung injury: Targeting a potential IL-1β/neutrophil extracellular traps feedback loop

Med Hypotheses. 2020 Oct:143:109906. doi: 10.1016/j.mehy.2020.109906. Epub 2020 May 30.


Most COVID-19 infected individuals present with mild flu-like symptoms; however, 5-10% of cases suffer from life-threatening pneumonia and respiratory failure. The pathogenesis of SARS-CoV-2 and its pathology of associated acute lung injury (ALI), acute respiratory distress syndrome (ARDS), sepsis, coagulopathy and multiorgan failure is not known. SARS-CoV-2 is an envelope virus with S (spike), M (membrane), N (nucleocapsid) and E (envelop) proteins. In a closely related coronavirus (SARS-CoV), the transmembrane E protein exerts an important role in membrane-ionic transport through viroporins, deletion of which reduced levels of IL-1β and a remarkably reduced lung edema compared to wild type. IL-1β is generated by macrophages upon activation of intracellular NLRP3 (NOD-like, leucine rich repeat domains, and pyrin domain-containing protein 3), part of the functional NLRP3 inflammasome complex that detects pathogenic microorganisms and stressors, while neutrophils are enhanced by increasing levels of IL-1β. Expiring neutrophils undergo "NETosis", producing thread-like extracellular structures termed neutrophil extracellular traps (NETs), which protect against mild infections and microbes. However, uncontrolled NET production can cause acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), coagulopathy, multiple organ failure, and autoimmune disease. Herein, we present arguments underlying our hypothesis that IL-1β and NETs, mediated via NLRP3 inflammasomes, form a feed-forward loop leading to the excessive alveolar and endothelial damage observed in severe cases of COVID-19. Considering such assertions, we propose potential drug candidates that could be used to alleviate such pathologies. Considering that recent efforts to ascertain effective treatments of COVID-19 in severe patients has been less than successful, investigating novel avenues of treating this virus are essential.

Keywords: COVID19; Coronavirus; Inflammasomes; Neutrophil extracellular traps (NETs); SARS.

MeSH terms

  • Acute Lung Injury / drug therapy*
  • Acute Lung Injury / etiology*
  • Acute Lung Injury / immunology
  • Betacoronavirus*
  • COVID-19
  • COVID-19 Drug Treatment
  • Coronavirus Infections / complications*
  • Coronavirus Infections / drug therapy*
  • Coronavirus Infections / immunology
  • Extracellular Traps / drug effects*
  • Extracellular Traps / immunology
  • Feedback, Physiological
  • Humans
  • Inflammasomes / immunology
  • Interleukin-1beta / antagonists & inhibitors*
  • Interleukin-1beta / immunology
  • Models, Biological
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology
  • Pandemics
  • Pneumonia, Viral / complications*
  • Pneumonia, Viral / drug therapy*
  • Pneumonia, Viral / immunology
  • SARS-CoV-2


  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human