Abstract
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.
Highlights
In recent years, there has been an explosion of interest in the innate immune response [1,2,3,4,5] because it is known that most infectious pathogens are eliminated through the innate immune response without necessarily requiring the activation of adaptive immunity [6,7,8]
When n1 and n2 are greater than 1, a large delay t1 or t4 can make the system stable (Figure 14). These results demonstrated that an adaptable time delay for viral replication and IFN feedback regulation will control the dynamics of the system even if the delays of the other reaction processes affect the innate immune system, further suggesting the importance of two processes for viral replication and IFN feedback regulation
By combining the theoretical analysis with experiment study, we find that the replication ratio of the virus is an important parameter for resulting in viral infection, virus-clearance and steady-state maintenance
Summary
There has been an explosion of interest in the innate immune response [1,2,3,4,5] because it is known that most infectious pathogens are eliminated through the innate immune response without necessarily requiring the activation of adaptive immunity [6,7,8]. In the early phase of viral infection, IFN-regulatory factor 3 (IRF3) and IRF7 are phosphorylated at specific serine residues, resulting in the homodimerization or heterodimerization of the IRF3 and IRF7 These dimers translocate to the nucleus and induce the expression of chemokines and small amounts of IFNb (and IFNa). The IFNs induce the transcription of the IRF7 gene, leading to increases in the expression of the IFNb and IFNa proteins and, promoting the production of many antiviral proteins (such as Mx, ISG20, OAS and PKR) and immunoactive cytokines These antiviral components inhibit viral replication and cause apoptosis of infected cells, subsequently resulting in the clearance of the infectious pathogens
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