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Author Spotlight: Unveiling the Polyfunctionality and Heterogeneity in Immune Responses

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Characterizing the Crosstalk Between Programmed Cell Death Pathways in Cytokine Storm With an Agent-Based Model.

Solomon Feuerwerker¹, R Chase Cockrell², Gary An¹

¹Department of Surgery, University of Vermont Larner College of Medicine, Burlington, Vermont, USA.

Surgical Infections

|October 12, 2023

Summary

This summary is machine-generated.

Programmed cell death pathways (PCDPs) show complex crosstalk, aiding pathogen defense but complicating cytokine storm (CS) treatment. Computational modeling reveals redundancies challenge immunomodulation therapies for CS.

Keywords:

agent-based model cytokine storm host-pathogen interactions programmed cell death sepsis

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Published on: September 15, 2023

Area of Science:

Immunology
Computational Biology
Pathogen Response

Background:

Programmed cell death pathways (PCDPs), including apoptosis, pyroptosis, and necroptosis, exhibit extensive crosstalk, creating a redundant host defense system.
While beneficial against diverse pathogens, the inflammatory nature of pyroptosis and necroptosis complicates therapeutic control of cytokine storm (CS)-induced organ dysfunction.

Purpose of the Study:

To develop a computational model simulating the crosstalk between PCDPs.
To enhance understanding of PCDP interactions during microbial infections and evaluate potential therapeutic interventions for CS.

Main Methods:

A literature review of apoptosis, pyroptosis, and necroptosis was conducted.
An agent-based model, the programmed cell death agent-based model (PCDABM), was developed using NetLogo.
Simulations involved microbial infections (IAV, EPEC, SE), silencing of PCDPs, and blockade of TNF and IL-1.

Main Results:

The PCDABM successfully simulated cross-activation of PCDPs and microbial clearance for IAV, EPEC, and SE infections.
Simulations blocking TNF and IL-1 failed to reduce systemic damage, indicating limitations in targeting these pathways for CS.

Conclusions:

Host PCDP redundancies are crucial for broad-spectrum pathogen defense but pose challenges for immunomodulatory therapies targeting CS.
Integrative simulation models like PCDABM are valuable for identifying therapeutic targets to mitigate CS while preserving host defense.