Abstract
Influenza A virus (IAV) infection exhibits reproducible within-host viral kinetics, yet the immune mechanisms that generate these trajectories are difficult to infer from aggregate measurements alone. This thesis uses comparative mechanistic modeling to identify immune processes that govern two key outcomes of within-host IAV infection: late-phase viral control following peak burden and spatial containment of focal spread in lung tissue. We focus on young versus aged mice to probe age-dependent differences in adaptive control, and on spatially explicit models to capture containment phenomena that are not represented in well-mixed descriptions. First, we develop and compare ODE models for coupled virus and influenza-specific CD8+ T cell dynamics in young versus aged mice. Calibration and model selection support stronger CD8+ expansion and stronger downregulation in young mice, versus weaker expansion and impaired downregulation in aged mice, implicating age-dependent differences in the CD8+ effector program as a driver of late-phase infection control.
Second, we develop a spatial 2D reaction-diffusion models that extend a target-cell-limited framework with an explicit type I interferon (IFN) field and alternative IFN-mediated containment mechanisms. Calibrated to aggregate virus and IFN data with qualitative spread constraints, model selection favors IFN positive feedback for matching bulk dynamics. Bulk trajectories alone do not uniquely identify which additional IFN antiviral pathway is operative; imposing qualitative criteria for containment and clearance narrows support toward IFN-mediated suppression of viral production and/or infectivity.