A single-cell mathematical model of SARS-CoV-2 induced pyroptosis and the anti-inflammatory response to the drug tranilast

Hamis, Sara J; Macfarlane, Fiona R

Pyroptosis is an inflammatory mode of cell death that contributes to the cytokine storm associated with severe cases of coronavirus disease 2019 (COVID-19). Central to pyroptosis induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the formation of the NLRP3 inflammasome. Inflammasome formation, and by extension pyroptosis, may be inhibited by certain anti-inflammatory drugs. One such drug, tranilast, is currently being evaluated as a COVID-19 treatment target in a clinical trial. In this study, we present a single-cell mathematical model that captures the formation of the NLRP3 inflammasome, pyroptotic cell death and drug-responses to tranilast. The model is formulated in terms of a system of ordinary differential equations (ODEs) that describe the dynamics of proteins involved in pyroptosis. The model demonstrates that tranilast delays the formation of the NLRP3 inflammasome, and thus may alter the mode of cell death from inflammatory (pyroptosis) to non-inflammatory (e.g., apoptosis).