title: 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.
authors.affiliation: Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. dishi@nagasaki-u.ac.jp
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ishibashi
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Atarashi
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Nishida
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018620:PrPSc Proteins / Q000235:genetics / Q000378:metabolism; D017096:Prion Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050838:Interferon Regulatory Factor-3; D053594:Myeloid Differentiation Factor 88; D018620:PrPSc Proteins; D051193:Toll-Like Receptors