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

Abstract

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.

Fig. 1

Schematic visualisation of the proposed mechanism underlying increased Neutrophil Extracellular Trap (NET) production in response to SARS-CoV-2 infection, mediated via NLRP3 inflammasomes and elevated production of IL-1β, presented chronologically (steps 1–8). Viral infection expresses E-protein/viroporins, which increase ionic influx, enhancing NLRP3 expression and increased formation of NLRP3 inflammasome complexes within the macrophage. Elevated levels of inflammasomes cause an increase in cleavage of pro-IL-1$\beta$ to IL-1$\beta$ via elevated production of caspases. The increased levels of IL-1$\beta$ will enter a ‘feedforward loop’ with the NLRP3 inflammasome (dotted line), and further activate higher levels of Neutrophils, resulting in elevated levels of NET production. Such highly increased NET levels will result in increased clot formation, endothelial damage, and alveolar damage associated with COVID-19. Potential drug candidates (red text) are displayed in appropriate areas where inhibition (red lines) of this proposed mechanism could take place. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)