Severe COVID-19: NLRP3 Inflammasome Dysregulated

Abstract

SARS-CoV-2 might directly activate NLRP3 inflammasome resulting in an endogenous adjuvant activity necessary to mount a proper adaptive immune response against the virus. Heterogeneous response of COVID-19 patients could be attributed to differences in not being able to properly downregulate NLRP3 inflammasome activation. This relates to the fitness of the immune system of the individual challenged by the virus. Patients with a reduced immune fitness can demonstrate a dysregulated NLRP3 inflammasome activity resulting in severe COVID-19 with tissue damage and a cytokine storm. We sketch the outlines of five possible scenarios for COVID-19 in medical practice and provide potential treatment options targeting dysregulated endogenous adjuvant activity in severe COVID-19 patients.

The role of host genetics in susceptibility to severe viral infections in humans and insights into host genetics of severe COVID-19: A systematic review

“…There are different platforms for Inflammasome activation including nucleotide-binding oligomerization domain (NOD), leucine-rich repeat (LRR)-containing protein (NLR) family members NLRP1, NLRP3, and NLRC4 ( Broz and Dixit, 2016 ). Inflammasome activation is one of the main theories for explanation of the cytokine storm during COVID-19 causing severe manifestations in around 15 % of the infected population ( van den Berg and te Velde, 2020 ; Rodrigues et al, 2020 ; Freeman and Swartz, 2020 ). NLRP3 activation in COVID-19 patients was proven in vitro in PBMCs and tissues of COVID-19 patients.…”

Dexmedetomidine: another arrow in the quiver to fight COVID-19 in intensive care units

“…inflammasome, NFκB and JAK/STAT signaling pathways [14][15][16][17][18] that may be responsible for feedforward interactions between neutrophils and macrophages stimulating netosis and aggravating organ damage during SARS-CoV-2 infection [8][9][10] . Dexmedetomidine-mediated activation of cholinergic pathways and decreased sympathetic tone confers additional cytoprotective and antiinflammatory benefits.…”

“…Dexmedetomidine, a selective α 2 adrenergic receptor agonist, has been studied extensively for long-term intensive care unit (ICU) use. [2][3][4][5][6] Based on studies investigating its effects in reducing sepsis-related lung injury and ischaemia-reperfusion injury of heart, kidney, brain, and intestine (organs commonly affected in COVID-19), 7 and based on the mechanistic models of COVID-19 pathogenesis, [8][9][10][11] we suggest that dexmedetomidine may have therapeutic potential in COVID-19. Our hypothesis is supported by a case report of improved oxygenation with dexmedetomidine in a COVID-19 patient, 12 as well as by another encouraging report 13 .…”

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 ].…”