Interferon-Stimulated Gene-Mediated Defense Against Prion Infection: Noncanonical Function of Oas1a

Prion diseases are invariably fatal neurodegenerative disorders characterized by the conformational conversion of the host-encoded prion protein (PrP^C) into its misfolded, pathogenic isoform (PrP^Sc). Unlike conventional infectious agents such as viruses, prions lack nucleic acids, leading to the long-held assumption that they escape immune surveillance. Accumulating evidence, however, challenges this view and implicates the innate immune system in shaping prion pathogenesis. Yet, the underlying molecular mechanisms remain incompletely defined. Among innate immune pathways, our studies have implicated type I interferons (I-IFN), traditionally recognized as antiviral mediators, in the regulation of prion propagation and disease progression. We demonstrated that IRF3, a central transcriptional activator of I-IFN, restricts prion propagation and delays the onset of disease. Moreover, I-IFN itself enhances cellular resistance to prion infection in both in vitro and in vivo systems. Our recent work identified 2'-5'-oligoadenylate synthetase 1A (Oas1a), a downstream effector induced by I-IFN, as a mediator of noncanonical anti-prion activity. Genetic deletion of Oas1a increases susceptibility to prion infection, whereas recombinant Oas1a or enforced expression of Oas1a restores resistance. Oas1a blocks prion propagation by directly binding to PrP^C and interfering with its conversion into PrP^Sc. This protective activity depends on Oas1a oligomerization, but not on its canonical 2'-5'-oligoadenylate synthetase activity. Collectively, these findings support a model in which the IRF3-I-IFN-Oas1a axis contributes to host defense against prion infection, at least in the experimental systems examined to date. In this review, we highlight current evidence for the involvement of this axis in innate immune responses to prion infection and discuss its mechanistic and potential therapeutic implications.