Characterizing the crosstalk between programmed cell death pathways in cytokine storm with an agent-based model

Author(s):
Solomon Feuerwerker; Gary An

Background:

Programmed cell death pathways (PCDPs), such as apoptosis, pyroptosis, and necroptosis, are critical components of host defense against infection. Though initially studied individually, there is an increasing recognition of extensive crosstalk between PCDPs, resulting in a highly redundant system responsive to a breadth of potential pathogens. However, since pyroptosis and necroptosis propagate inflammation, these redundancies also present challenges for therapeutic control of dysregulated hyperinflammation seen in cytokine storm generated organ dysfunction.

Hypothesis:

We hypothesize that the conversion of static diagrams that embody existing knowledge regarding apoptosis, pyroptosis, and necroptosis into simulation models can enhance our understanding of the dynamics of the crosstalk between PCDPs.

Methods:

Literature regarding apoptosis, pyroptosis, and necroptosis was reviewed and transposed into an agent-based model, the Programmed Cell Death Agent Based Model (PCDABM). Computational experiments were performed to simulate the activation of various PCDPs as seen by differing microbes, specifically: Salmonella enterica, Enteropathic Escherichia coli (EPEC), and Influenza A virus (IAV). The potential protective value of PCDP crosstalk was evaluated by silencing either pyroptosis, necroptosis, or both. Computational experiments were also performed simulating the effect of potential therapies blocking Tumor Necrosis Factor (TNF) and Interleukin-1 (IL-1).

Results:

The PCDABM was implemented in the agent-based modeling toolkit NetLogo. Computational experiments of infection with S enterica, EPEC and IAV reproduced cross-activation of PCDPs with effective microbial clearance. Silencing inflammation-propagating PCDPs (pyroptosis and necroptosis) reduced the ability to effectively clear infection. Simulations of anti-TNF and anti-IL-1 did not significantly reduce the aggregated amount of inflammation-generated system damage, the surrogate for cytokine storm-generated tissue damage.

Conclusions:

Significant redundancies have evolved in host PCDPs in order to maintain protection against a wide range of pathogens. However, these redundancies also challenge attempts at dampening the pathogenic hyperinflammatory state of cytokine storm using therapeutic immunomodulation. Integrative simulation models such as the PCDABM can aid in identifying potentially targetable inflection points that can mitigate cytokine storm while maintaining effective host defense.