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

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.