Decoding the dynamics of multilayered stochastic antiviral IFN-I responses

Type I Interferon (IFN-I) responses were first recognized for their role in antiviral immunity, but it is now widely appreciated that IFN-Is have many immunomodulatory functions, influencing antitumor responses, autoimmune manifestations, and antimicrobial defenses. Given these pivotal roles, it may be surprising that multilayered stochastic events create highly heterogeneous, but tightly regulated, all-or-nothing cellular decisions. Recently, mathematical models have provided crucial insights into the stochastic nature of antiviral IFN-I responses, which we critically evaluate in this review. In this context, we emphasize the need for innovative single-cell technologies combined with mathematical models to further reveal, understand, and predict the complexity of the IFN-I system in physiological and pathological conditions that may be relevant to a plethora of diseases.