The investigation of the dynamics and regulation of virus-triggered innate immune signaling pathways at a system level will enable comprehensive analysis of the complex interactions that maintain the delicate balance between resistance to infection and viral disease. In this study, we developed a delayed mathematical model to describe the virus-induced interferon (IFN) signaling process by considering several key players in the innate immune response. Using dynamic analysis and numerical simulation, we evaluated the following predictions regarding the antiviral responses: (1) When the replication ratio of virus is less than 1, the infectious virus will be eliminated by the immune system’s defenses regardless of how the time delays are changed. (2) The IFN positive feedback regulation enhances the stability of the innate immune response and causes the immune system to present the bistability phenomenon. (3) The appropriate duration of viral replication and IFN feedback processes stabilizes the innate immune response. The predictions from the model were confirmed by monitoring the virus titer and IFN expression in infected cells. The results suggest that the balance between viral replication and IFN-induced feedback regulation coordinates the dynamical behavior of virus-triggered signaling and antiviral responses. This work will help clarify the mechanisms of the virus-induced innate immune response at a system level and provide instruction for further biological experiments.

In this paper, we investigate the complex dynamical behaviors of a biological network that is derived from innate immune responses and that couples positive and negative feedback loops. The stability conditions of the non-negative equilibrium points (EPs) of the system are obtained, using the theory of dynamical systems, and we deduce that no more than three stable EPs exist in this system. Through bifurcation analysis and numerical simulations, we find that the system presents rich dynamical behaviors, such as monostability, bistability and oscillations. These results reveal how positive and negative feedback cooperatively regulate the dynamical behavior of the system.

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