Protective role of MyD88-independent innate immune responses against prion infection

Abstract

Despite recent progress in the understanding of prion diseases, little is known about the host-defense mechanisms against prion. Although it has long been thought that type I interferon (IFN-I) has no protective effect on prion infection, certain key molecules in innate immunity such as toll-like receptor (TLR) 4 seemed to be involved in the host response. For this reason we decided to focus on TLRs and investigate the role of a transcription factor, interferon regulatory factor 3 (IRF3), because the absence of MyD88, a major adaptor signaling molecule of TLRs, has no effect on the survival of prion infected mice. Intriguingly, survival periods of prion inoculated IRF3-knockout mice became significantly shorter than those of wild-type mice. In addition, IRF3 stimulation inhibited PrP^Sc replication in prion persistently-infected cells, and a de novo prion infection assay revealed that IRF3-overexpression could make host cells resistant to prion infection. Our work suggests that IRF3 may play a key role in innate immune responses against invasion of prion pathogens. Activated IRF3 could upregulate several anti-pathogen factors, including IFN-I, and induce sequential responses. Although the mechanism for the anti-prion effects mediated by IRF3 has yet to be clarified, certain interferon responsive genes might be involved in the anti-prion host-defense mechanism.

Keywords: :

• prion
• innate immunity
• interferon regulatory factor 3 (IRF3)
• type I interferon (IFN)
• host defense

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Acknowledgments

We thank Drs. Katsuya Satoh, Naohiro Yamaguchi, Takayuki Fuse, Hitoki Yamanaka, Takehiro Matsubara and Kazunori Sano for helpful discussions; graduate students Takehiro Nakagaki, Takujiro Homma, Hanae Takatsuki and Kaori Ono-Ubagai for assistance with experiments; and Mari Kudo, Ayumi Yamakawa and Atsuko Matsuo for technical assistance. This work was supported in part by the global COE Program (F12); a grant-in-aid for science research (C) (No. 24591482) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; a grant for BSE research, and a grant-in-aid of the Research Committee of Prion disease and Slow Virus Infection, from the Ministry of Health, Labor and Welfare of Japan.