The Inflammasome in Times of COVID-19

Juan Carlos de Rivero Vaccari, W Dalton Dietrich, Robert W Keane, Juan Pablo de Rivero Vaccari, Juan Carlos de Rivero Vaccari, W Dalton Dietrich, Robert W Keane, Juan Pablo de Rivero Vaccari

Abstract

Coronaviruses (CoVs) are members of the genus Betacoronavirus and the Coronaviridiae family responsible for infections such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and more recently, coronavirus disease-2019 (COVID-19). CoV infections present mainly as respiratory infections that lead to acute respiratory distress syndrome (ARDS). However, CoVs, such as COVID-19, also present as a hyperactivation of the inflammatory response that results in increased production of inflammatory cytokines such as interleukin (IL)-1β and its downstream molecule IL-6. The inflammasome is a multiprotein complex involved in the activation of caspase-1 that leads to the activation of IL-1β in a variety of diseases and infections such as CoV infection and in different tissues such as lungs, brain, intestines and kidneys, all of which have been shown to be affected in COVID-19 patients. Here we review the literature regarding the mechanism of inflammasome activation by CoV infection, the role of the inflammasome in ARDS, ventilator-induced lung injury (VILI), and Disseminated Intravascular Coagulation (DIC) as well as the potential mechanism by which the inflammasome may contribute to the damaging effects of inflammation in the cardiac, renal, digestive, and nervous systems in COVID-19 patients.

Keywords: COVID-19; IL-1beta; caspase-1; coronavirus; inflammasome; inflammation.

Copyright © 2020 de Rivero Vaccari, Dietrich, Keane and de Rivero Vaccari.

Figures

Figure 1
Figure 1
Structure of coronaviruses. In a lipid bilayer envelope, CoVs consist of a spike (S) protein, a membrane (M) protein and an envelope (E) protein. Inside the lipid bilayer envelope, the nucleocapsid (N) protein and the genomic RNA comprise the inner core.
Figure 2
Figure 2
Mechanisms of inflammasome activation. Inflammasome activation in general relies on two signals for its activation. First, a PAMP binds to a PRR resulting in synthesis of NLRP3 and pro-IL-1β. Then a second signal leads to inflammasome assembly, leading to the activation of caspase-1, processing of pro-IL-1β into IL-1β and pyroptosis. The second signal may come from a variety of pathways including K+ efflux. Lysosomal rupture or mitochondrial dysfunction. Mitochondrial dysfunction results in release of ROS, Ca2+ and mitochondrial DNA (mtDNA), all of which have been shown to activate the inflammasome. Pyroptosis occurs as a result of caspase-1-mediated cleavage of GSDM-D at the linker region of GSDM-D. Following GSDM-D cleavage, the amino terminus of GSDM-D (GSDM-D-N) forms a non-selective pore at the cell membrane through which IL-1β is then released.
Figure 3
Figure 3
Mechanisms of inflammasome activation in CoV infection. In the lungs when the S protein of SARS-CoV-2 binds to the ACE2 receptor, the virus is internalized by endocytosis, leading to translation and RNA replication of genomic and sub-genomic RNA including ORF3a, ORF8b, and the viral structural proteins (N, S, M, and E proteins). The E protein is involved in Ca2+ release from the Golgi apparatus. This Ca2+ has the potential to activate the inflammasome. In addition, ORF3a interacts with TRAF3 to ubiquitinate ASC, and ORF8b interacts with NLRP3, resulting in inflammasome activation and pyroptosis. IL-1β is released through the GSDM-D-N pore during pyroptosis, while Na+ and H2O molecules enter the cell, resulting in cell swelling, which then manifests as pulmonary edema. Furthermore, ORF3a also acts in the cell membrane as a K+ channel, which causes an ionic imbalance also capable of promoting inflammasome activation, and mitochondrial dysfunction produces ROS that also contribute to inflammasome activation.
Figure 4
Figure 4
Role of the inflammasome on clot formation. Thrombin binds to a GPCR in platelets, resulting in ROS-dependent activation of the inflammasome and release of IL-1β into the cell. IL-1β stimulates production of IL-6. IL-6 stimulates tissue factor (TF) to convert prothrombin into thrombin. TF-containing microvesicles are released by pyroptosis following inflammasome activation. Thrombin then converts fibrinogen into fibrin, leading to fibrin cross-linking, clot formation and DIC.

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