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Prion diseases, including human Creutzfeldt-Jakob disease, are infectious, intractable central neurodegenerative diseases, which are also zoonoses that commonly infect not only higher organisms but also a wide variety of animals.Pathogenic prions induce abnormal prion protein (PrP), which is produced by structural conversion of normal PrP, a beta-sheet-rich structure with high aggregation propensity. Thus, it is believed that the host is immunotolerant against prions because there is no difference in the primary structure of normal and abnormal PrP, and prions do not induce a marked immune response. Recently, using mutated Toll-like receptor (TLR) 4-transgenic mice, a bioassay after prion inoculation has intriguingly found that the TLR4-signaling pathway may have a protective role against prion infection. Meanwhile, we reported that a transcription factor, interferon regulatory factor-3 (IRF-3), located downstream of TLR4 signaling, showed resistance to prions. IRF-3-inducing type I interferon (I-IFN) is a critical factor for the host defense against pathogen invasion. These findings indicate that the TLR-signaling pathway of the innate immune system might regulate prion invasion. However, the details have not been fully determined. In this symposium, we will introduce new findings including the relationship between I-IFN and prions., Journal of the Pharmaceutical Society of Japan, 139(7), pp.993-998; 2019