Mathematical Analysis of Receptor-Mediated Immune Cell Death in Innate Antiviral Immunity

Apoptosis is a series of complex biochemical processes of programmed cell death which occurs in multicellular organisms. This mechanism must be highly regulated and controlled; otherwise, harmful illness such as cancer and autoimmune diseases may occur.  Apoptosis is a key mechanism during a typical viral immune response.In the course of an infection, this mechanism eliminates infected cells and by that,limits the resources for viral replication.  Recently, regulation of the death recep-tor pathway by cFLIP, a key regulator of signaling complexes downstream of death receptors, was targeted experimentally to study the role of apoptosis in influenza A virus (IAV) infection. By increasing the expression level of cFLIP in transgenic mice, a higher accumulation of Natural Killer (NK) cells and a higher viral load in comparison to wild type(WT) mice were observed. However, the viral load was similar in both mice after 10 days. Infection and functional impairment of NK cells was assumed to be responsible for the observed results.  In order to validate this hypothesis, a mathematical model was used to quantify the role of apoptosis medi-ated cell death in NK cells during the viral clearance. The model contains variables and parameters that represent population and interactions between healthy and in-fected epithelial cells, influenza A virions, healthy and infected NK cells. Several simplifications were made in order to better estimate the critical parameters of the model. Simulation results showed that infection of NK cells with a longer lifespan alone cannot explain the observed high viral load. However, by increasing the viral production of infected NK cells, the viral load data was fitted. The lack of caspase3, due to the over-expression of cFLIP, may contribute to higher viral production inNK cells. Furthermore, a shorter lifespan of healthy NK cells was predicted, which may be related to biological exhaustion due to higher infection level. The posteriors and the correlation analysis of the parameters showed that parameters associated with lifespan and the viral production of infected NK cells are linearly correlated.