Mathematical Modeling Identifies the Role of Adaptive Immunity as a Key Controller of Respiratory Syncytial Virus (RSV) Titer in Cotton Rats

Abstract

Respiratory syncytial virus (RSV) is a common virus that can have varying effects ranging from mild cold-like symptoms to mortality depending on the age and immune status of the individual. We combined mathematical modeling using ordinary differential equations (ODEs) with measurement of RSV infection kinetics in primary well differentiated human airway epithelial (HAE) cultures in vitro and in immunocompetent and immunosuppressed cotton rats to glean mechanistic details that underlie RSV infection kinetics in the lung. Quantitative analysis of viral titer kinetics in our mathematical model showed that the elimination of infected cells by the adaptive immune response generates unique RSV titer kinetic features including a faster time scale of viral titer clearance than viral production, and a monotonic decrease in the peak RSV titer with decreasing inoculum dose. Parameter estimation in the ODE model using a non-linear mixed effects approach revealed a very low rate (average single cell lifetime > 10 days) of cell lysis by RSV before the adaptive immune response is initiated. Our model predicted negligible changes in the RSV titer kinetics on earlier days (< 5 d.p.i) but a slower decay in RSV titer in immunosuppressed cotton rats compared to that in nonsuppressed cotton rats at later days (>5 d.p.i) in silico. These predictions were in excellent agreement with the experimental results. Our combined approach quantified the importance of the adaptive immune response in suppressing RSV infection in cotton rats, which could be useful in testing RSV vaccine candidates. ImportanceA major difficulty in developing vaccines against RSV infection is our rudimentary understanding of the mechanisms that underlie RSV infection. We addressed this challenge by developing a mechanistic computational model with predictive powers for describing RSV infection kinetics in cotton rats. The model was constructed synergistically with in vitro and in vivo measurements. The combined framework determined an important role for CD8+ T cells responses in reducing RSV titers in cotton rats. The framework can be used to design future experiments to elucidate mechanisms underlying RSV infection and test outcomes for potential vaccine candidates. In addition, estimation of the model parameters provides quantitative values for parameters of biological and clinical interest such as the replication rate of RSV, the death rate of infected cells, and the average number of new infections initiated by a single infected cell. † Equal contribution * Corresponding authors