Inflammasomes and Pyroptosis as Therapeutic Targets for COVID-19

Abstract

The inflammatory response to severe acute respiratory syndrome-related coronavirus 2 infection has a direct impact on the clinical outcomes of coronavirus disease 2019 patients. Of the many innate immune pathways that are engaged by severe acute respiratory syndrome-related coronavirus 2, we highlight the importance of the inflammasome pathway. We discuss available pharmaceutical agents that target a critical component of inflammasome activation, signaling leading to cellular pyroptosis, and the downstream cytokines as a promising target for the treatment of severe coronavirus disease 2019-associated diseases.

Figure 1.. Activation of the NLRP3 inflammasome by SARS coronavirus.

SARS-CoV E protein induces Ca²⁺ leakage to the cytosol from Golgi storage, while ORF3a induces K⁺ efflux at the plasma membrane to the extracellular spaces. These imbalance in the ionic concentration within the cells, and the resultant ROS generated by damaged mitochondria, triggers NLRP3 inflammasome activation. In addition to inducing K⁺ efflux, ORF3a promotes inflammasome assembly through TRAF3-mediated ubiquitination of ASC. ORF8b interacts directly with LRR of NLRP3 to stimulate its activation independent of ion channel activity. Inflammasome activation induces the formation of gasdermin-D pores on the cell membrane, causing IL-1β and IL-18 secretion, and the influx of water molecules leading to cell swelling and subsequent rupture (pyroptosis).