BPS2026 - Computational modeling of a circulating human neutrophil

Human neutrophils comprise 40%–70% of all circulating immune cells and are one of the body’s first responses to invading pathogens. Neutrophils exhibit a variety of behaviors that aid in fighting off infections such as degranulation, phagocytosis, recruitment/migration, and neutrophil extracellular trap formation. Although much progress has been made in elucidating these behaviors, there is still much that is unknown about their underlying molecular mechanisms. Computational models have proven useful in filling gaps in our knowledge, and generating predictions for future experiments, whereby our understanding of the mechanisms behind cellular behavior can be assessed. However, modeling the variety of behaviors exhibited by neutrophils requires significant computational efforts as these behaviors are regulated at various molecular levels (gene regulation, signal transduction, metabolic shifts, etc.) and emerge as a result of complex molecular interactions. Therefore, we propose the use of a whole-cell modeling (WCM) framework to more fully understand the molecular mechanisms that lead to complex neutrophil behaviors, and we present our initial efforts to generate a neutrophil WCM. We have generated a kinetic model of several core metabolic subsystems (e.g., glycolysis, oxidative phosphorylation, amino acid synthesis, etc.) using ordinary differential equations. This kinetic model of metabolism serves as a modular component of the human neutrophil WCM which interacts with simplified genetic information processing subsystems such as transcription and translation, which are treated stochastically using the chemical master equation (CME). We use this framework to investigate the activation dynamics of neutrophils by E-selectin molecules from inflamed endothelial cells and the subsequent downstream molecular cascade which results in the activation of both neutrophil integrins (such as lymphocyte function associated antigen-1) and the transcription factor NF-kB. Altogether, our work represents a significant step toward the generation of a neutrophil WCM that is able to recapitulate various immunity-related behaviors.