A single-cell mathematical model of SARS-CoV-2 induced pyroptosis and the effects of anti-inflammatory intervention

TL;DR

This paper introduces a mathematical model of SARS-CoV-2-induced pyroptosis at the single-cell level, showing how anti-inflammatory drugs can delay inflammasome formation and potentially shift cell death modes.

Contribution

The study develops a novel ODE-based single-cell model of pyroptosis and demonstrates its application in understanding anti-inflammatory interventions in COVID-19.

Findings

Anti-inflammatory drugs delay NLRP3 inflammasome formation

Model predicts shift from pyroptosis to apoptosis

Implementation in SARS-CoV-2 Tissue Simulator

Abstract

Pyroptosis is an inflammatory mode of cell death that can contribute to the cytokine storm associated with severe cases of coronavirus disease 2019 (COVID-19). The formation of the NLRP3 inflammasome is central to pyroptosis, which may be induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Inflammasome formation, and by extension pyroptosis, may be inhibited by certain anti-inflammatory drugs. In this study, we present a single-cell mathematical model that captures the formation of the NLRP3 inflammasome, pyroptotic cell death and responses to anti-inflammatory intervention that hinder the formation of the NLRP3 inflammasome. The model is formulated in terms of a system of ordinary differential equations (ODEs) that describe the dynamics of the biological components involved in pyroptosis. Our results demonstrate that an anti-inflammatory drug can delay the formation of the NLRP3 inflammasome, and thus may alter the mode of cell death from inflammatory (pyroptosis) to non-inflammatory e.g., apoptosis). The single-cell model is being implemented in a SARS-CoV-2 Tissue Simulator, in collaboration with a multidisciplinary coalition investigating within host-dynamics of COVID-19. In this paper, we provide an overview of the SARS-CoV-2 Tissue Simulator and highlight the effects of pyroptosis on a cellular level.