Targeting the NLRP3 Inflammasome in Severe COVID-19

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the genus Betacoronavirus within the family Coronaviridae. It is an enveloped single-stranded positive-sense RNA virus. Since December of 2019, a global expansion of the infection has occurred with widespread dissemination of coronavirus disease 2019 (COVID-19). COVID-19 often manifests as only mild cold-like symptomatology, but severe disease with complications occurs in 15% of cases. Respiratory failure occurs in severe disease that can be accompanied by a systemic inflammatory reaction characterized by inflammatory cytokine release. In severe cases, fatality is caused by the rapid development of severe lung injury characteristic of acute respiratory distress syndrome (ARDS). Although ARDS is a complication of SARS-CoV-2 infection, it is not viral replication or infection that causes tissue injury; rather, it is the result of dysregulated hyperinflammation in response to viral infection. This pathology is characterized by intense, rapid stimulation of the innate immune response that triggers activation of the Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathway and release of its products including the proinflammatory cytokines IL-6 and IL-1β. Here we review the literature that describes the pathogenesis of severe COVID-19 and NLRP3 activation and describe an important role in targeting this pathway for the treatment of severe COVID-19.

Immunomodulatory Effects of Diterpenes and Their Derivatives Through NLRP3 Inflammasome Pathway: A Review

“…The recent human threat SARS-CoV-2 is known to produce cytokine storm in Covid-19 patients. It is evident to release pro-inflammatory cytokines, including IL-6 and IL-1β through the NLRP3 inflammasome pathway (91). Many natural products and their derivatives, including diterpenes, have been found to act against human coronaviruses, such as SARS-CoV and the Middle East respiratory syndrome-related coronavirus (MERS-CoV) (92,93).…”

A 21st Century Evil: Immunopathology and New Therapies of COVID-19

“…Among them, IL-1b and TNF-a stand out for playing a central role in this context (26,156). The respiratory failure characteristic of SARS-CoV-2 infection, especially in individuals who develop the most severe forms of the disease, occurs independently of infection or viral replication in the epithelial bronchial cells and probably occurs due to exacerbated inflammatory dysregulation, resulting from activation of the NLRP3 inflammasome pathway and consequent release of IL-1b (158). However, although several articles have shown an increase in IL-1b production in COVID-19 patients and early treatment with IL-1 receptor blockers has helped prevent respiratory failure (159), its exact role in the immunopathogenesis of the disease has not yet been fully described.…”

ATP-Binding and Hydrolysis in Inflammasome Activation

“…Activating PAMP and DAMP signals for NLRP3 are famously diverse and include: K + efflux, Cl - efflux, Ca 2+ influx, mtDNA, alum, reactive oxygen species (ROS), implanted biomaterials or medical devices, asbestos, silica, calcium oxalate, and uric acid crystals, as well as a variety of metabolic components including cholesterol crystals and succinate accumulation [ 4 , 38 , 56 , 115 , 116 ]. Moreover, the NLRP3 inflammasome is thought to be a major pathophysiologic contributor to the cytokine storm observed in the clinical course of patients with COVID 19 [ 117 , 118 , 119 ]. There also exists a mechanism for non-canonical inflammasome activation involving caspase 4 and 5 in human, and caspase-11 (homologue) in mice [ 9 ].…”