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

Although we found that IFN expression remained unchanged in the brains of prion-infected mice during the terminal period, it has been reported that the expression of many interferon-stimulated genes was increased in the brains of prion-infected animals (Riemer et al., 2000; Xiang et al., 2004; Stobart et al., 2007) . Similarly, the expression of several interferon-stimulated genes was remarkably increased in the glial cells of the brains of patients with Creutzfeldt-Jakob disease (Baker et al., 2004) . However, it remains unclear whether IFN gene expression is increased in ex vivo and in vivo prion-infected models at an early phase. Furthermore, it has not been determined whether IFN in the host plays a protective role against prion pathogen infection. In our experiments, prion infection suppressed IFN expression in prion-infected cells (Fig. 1) and low IFN expression levels were recovered by a reduction of PrP Sc (Fig. 1) . Furthermore, pretreatment with IFN and IFN system stimuli inhibited the new establishment of prion infection (Fig. 2) , indicating that the host might combat prion propagation using any defence system available, including IFN. Thus, it will be necessary to investigate IFN induction at an early phase in neurons after prion infection. I-IFN stimulates various cell types, including immune cells such as lymphocytes, glia, and neurons (Delhaye et al., 2006; Paul et al., 2007) . Intriguingly, I-IFN is constitutively expressed at low levels even in the absence of pathogens and contributes to the regulation of tumour propagation and cell growth (Taniguchi and Takaoka, 2001) . Dysfunction of TLR4 and IRF3 facilitate prion pathogenesis (Spinner et al., 2008; Ishibashi et al., 2012a) , suggesting that this process might be negatively regulated by signalling pathways, including I-IFN, that act downstream of PRRs. Pretreatment with complete Freund's adjuvant and unmethylated CpG DNA to activate TLR signalling delays clinical onset in mice after prion inoculation (Sethi et al., 2002; Tal et al., 2003) . Furthermore, glial cells pretreated with poly I:C are strongly resistant to prion infection (Kang et al., 2016) , but post-treatment does not protect against prion pathogenesis in mice (Worthington, 1972; Cunningham et al., 2005; Field et al., 2010) . Here, we showed that I-IFN signalling mediated by IFNAR1 suppressed prion pathogenesis in cell culture and mouse models after prion inoculation. Although persistent infection by 22 L prion decreased expression of innate immunity genes such as Irf3 and Ifnb in an ex vivo system (Homma et al., 2014a) , I-IFN protected against primary prion infection in cells (Fig. 2) . These findings suggest that I-IFN, induced by TLR signalling, exerts a crucial anti-prion effect in the early phase after prion infection. Tumor necrosis factor-and interleukin-6, which are induced following stimulation of PRR such as TLR4, may contribute to the acceleration of prion infection as determined by a prion bioassay using gene-deficient mice (Thackray et al., 2004; Tamguney et al., 2008) . However, the relationship between suppression and I-IFN signalling has yet to be determined.