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Abstract

Upon viral infection, antiviral innate immunity pathways induce an antiviral state of host cells to infer with viral replication and spread. The RIG-I like receptor (RLR) family plays a crucial role by sensing pathogen-associated  molecular patterns (PAMPs) within the cytoplasm and triggering a signaling cascade leading to the expression of cytokines, most prominently type I and III interferons (IFNs). Upon secretion, IFNs trigger the expression of a large array of IFN stimulated genes (ISGs), which in concert establish a strongly antiviral state of the cell. In this study, we experimentally characterize the kinetic properties of RIG-I activation and the downstream signaling system and set up a mathematical model capable of accurately describing the dynamics from introduction of dsRNA to expression of ISGs upon IFN signaling. A previous study reported intriguing stochasticity in the activation of IRF7 upon virus infection of murine cells. Surprisingly, we found RIG-I signaling to be highly deterministic, suggesting that the previously observed stochasticity was largely due to staggered uptake of the stimulatory RNA during infection. Our time-resolved data was, hence, optimally suited to set up and calibrate a dynamic mathematical model of the core RIG-I pathway.  This model allows the identification of sensitive steps in the regulation of the immune response by directly linking them to the expression of interferon-stimulated genes (ISGs).  We validated this comprehensive pathway model by data from wildtype cells versus cells lacking the type I and III IFN system (IFNAR/IFNLR double knockout). Using additional activation dynamics of RIG-I pathway components in presence of viral antagonists, we identify the consequences of viral evasion strategies on the immune response and their most likely site-of-action. 

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