Immune Cell Dysfunction of SARS-CoV-2: Mathematical Modeling of the Within-Host Immune Dynamics

Abstract The COVID-19 pandemic has spurred extensive research into viral transmission and control, yet the mechanisms of the human immune response to SARS-CoV-2 remain incompletely understood, particularly the role of natural killer (NK) cells and cytokine regulation in disease severity. Mathematical modeling provides a powerful approach to bridge this gap by linking viral dynamics with immune interactions. In this work, we develop a mechanistic within-host model, formulated in a system of coupled ordinary and delayed differential equations, to investigate the contributions of NK cell activity, interferon signaling, and pro-inflammatory cytokines to viral clearance and disease outcome. Model parameters are estimated from experimental data, and computational simulations are used to explore how dysregulated NK responses and cytokine feedback loops may drive divergent clinical outcomes. Local sensitivity analysis identifies the most influential parameters shaping host–pathogen dynamics, highlighting potential control points for intervention. In addition, knockdown simulations are performed to mimic potential therapeutic interventions, allowing us to evaluate their advantages and limitations in silico. These findings provide mechanistic insights into COVID-19 immune dynamics and offer a foundation for guiding the design of future treatment strategies. Highlights We develop a within-host mathematical model of the SARS-CoV-2 immune response. The model incorporates key cytokines and immune cells including Natural Killer cells. Numerical simulations reproduce cytokine storms and NK cell dysfunction in severe disease. Sensitivity analysis identifies parameter impact and potential therapeutic interventions. Competing Interest Statement The authors have declared no competing interest. Footnotes Email addresses: kngoun{at}elon.edu (Pagnapech Ngoun), nalvarez2{at}elon.edu (Nicolas Alvarez), ayesh_awad{at}med.unc.edu (Ayesh Awad),