title: Protective role of interferon regulatory factor 3-mediated signaling against prion infection.
abstract: Abnormal prion protein (PrP(Sc)) generated from the cellular isoform of PrP (PrP(C)) is assumed to be the main or sole component of the pathogen, called prion, of transmissible spongiform encephalopathies (TSE). Because PrP is a host-encoded protein, acquired immune responses are not induced in TSE. Meanwhile, activation of the innate immune system has been suggested to partially block the progression of TSE; however, the mechanism is not well understood. To further elucidate the role of the innate immune system in prion infection, we investigated the function of interferon regulatory factor 3 (IRF3), a key transcription factor of the MyD88-independent type I interferon (IFN) production pathway. We found that IRF3-deficient mice exhibited significantly earlier onset with three murine TSE strains, namely, 22L, FK-1, and murine bovine spongiform encephalopathy (mBSE), following intraperitoneal transmission, than with wild-type controls. Moreover, overexpression of IRF3 attenuated prion infection in the cell culture system, while PrP(Sc) was increased in prion-infected cells treated with small interfering RNAs (siRNAs) against IRF3, suggesting that IRF3 negatively regulates PrP(Sc) formation. Our findings provide new insight into the role of the host innate immune system in the pathogenesis of prion diseases.
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: Takayuki
authors.initials: T
authors.lastname: Fuse
authors.forename: Takehiro
authors.initials: T
authors.lastname: Nakagaki
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Katsuya
authors.initials: K
authors.lastname: Satoh
authors.forename: Kenya
authors.initials: K
authors.lastname: Honda
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Nishida
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism / Q000473:pathology
chemical_list: D050838:Interferon Regulatory Factor-3; D018620:PrPSc Proteins