Type I interferon protects neurons from prions in in vivo models

Ishibashi, Daisuke; Homma, Takujiro; Nakagaki, Takehiro; Fuse, Takayuki; Sano, Kazunori; Satoh, Katsuya; Mori, Tsuyoshi; Atarashi, Ryuichiro; Nishida, Noriyuki

Viral and bacterial pathogens induce various immunological responses in the host to eliminate foreign pathogens from the body. Because the amino acid sequence of PrP Sc is identical to that of PrP C , which is encoded by a host gene, the host immune system was initially thought not to recognize the prion pathogen (Aguzzi and Polymenidou, 2004) . However, accumulated evidence has shown that prion infection stimulates pattern recognition receptor (PRR)related molecules and related signalling pathways, including Toll-like receptors (TLRs), interferon regulatory factors (IRFs), and some cytokines (Prinz et al., 2003; Spinner et al., 2008; Bradford and Mabbott, 2012; Ishibashi et al., 2012a; Nuvolone et al., 2015; Kang et al., 2016) . We have also reported that IRF3, which upregulates type I interferon (I-IFN) in various cell types, including neurons, plays a role in host defence against prion infection (Ishibashi et al., 2012a, b) , and that persistent prion infection negatively regulates IRF3 via suppression of the transcription factor Octamer-binding protein-1 (Oct-1) (Homma et al., 2014a) . Prions also exhibit strain diversity and reciprocal interference between strains, analogous to viral infections (Dickinson et al., 1972 (Dickinson et al., , 1975 Manuelidis, 1998) . In addition, the levels of interferon-stimulated genes with anti-viral functions, including myxovirus resistance protein, protein kinase R, and 2 0 -5 0 oligoadenylate synthetase, are significantly elevated at the clinical stage of prion disease in animal models (Riemer et al., 2000; Baker et al., 2004; Xiang et al., 2004; Stobart et al., 2007) , suggesting that innate immunity protects the host, at least partially, against prion infection. In this study, we focused on the relationship between I-IFN and prion disease and sought to determine which interferon-stimulated gene induced by I-IFN signalling plays a direct protective role against prion invasion.