Abstract
Myriad experiments have identified an important role for CD8+ T cell response mechanisms in determining recovery from influenza A virus infection. Animal models of influenza infection further implicate multiple elements of the immune response in defining the dynamical characteristics of viral infection. To date, influenza virus models, while capturing particular aspects of the natural infection history, have been unable to reproduce the full gamut of observed viral kinetic behavior in a single coherent framework. Here, we introduce a mathematical model of influenza viral dynamics incorporating innate, humoral, and cellular immune components and explore its properties with a particular emphasis on the role of cellular immunity. Calibrated against a range of murine data, our model is capable of recapitulating observed viral kinetics from a multitude of experiments. Importantly, the model predicts a robust exponential relationship between the level of effector CD8+ T cells and recovery time, whereby recovery time rapidly decreases to a fixed minimum recovery time with an increasing level of effector CD8+ T cells. We find support for this relationship in recent clinical data from influenza A (H7N9) hospitalized patients. The exponential relationship implies that people with a lower level of naive CD8+ T cells may receive significantly more benefit from induction of additional effector CD8+ T cells arising from immunological memory, itself established through either previous viral infection or T cell-based vaccines.
Highlights
Invasion of influenza virus into a host’s upper respiratory tract leads to infection of healthy epithelial cells and subsequent production of progeny virions [1]
The primary driver for the maintenance of the target cell pool during acute viral infection is a timely activation of the innate immune response (Figure S2 in Supplementary Material), indicating that our model improves upon previous models where viral clearance was only achieved through depletion of target cells
We find that our model (with parameters calibrated against Miao et al.’s data [38]) is able to reproduce these observations: FIGURE 4 | The model solution exhibits three-phase behavior following influenza virus infection. (A) Schematic representation of three phases of behavior based on involvement of immune responses
Summary
Invasion of influenza virus into a host’s upper respiratory tract leads to infection of healthy epithelial cells and subsequent production of progeny virions [1]. A recent study of human influenza A (H7N9) hospitalized patients has implicated the number of effector CD8+ T cells as an important driver of the duration of infection [21] These diverse experimental and clinical data, sourced from a number of host species, indicate that timely activation and elevation of CD8+ T cell levels may play a major role in the rapid and successful clearance of influenza virus from the host. These observations motivate our modeling study of the role of CD8+ T cells in influenza virus clearance
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