title: Accelerated prion disease pathogenesis in Toll-like receptor 4 signaling-mutant mice.
abstract: Prion diseases such as scrapie involve the accumulation of disease-specific prion protein, PrP(Sc), in the brain. Toll-like receptors (TLRs) are a family of proteins that recognize microbial constituents and are central players in host innate immune responses. The TLR9 agonist unmethylated CpG DNA was shown to prolong the scrapie incubation period in mice, suggesting that innate immune activation interferes with prion disease progression. Thus, it was predicted that ablation of TLR signaling would result in accelerated pathogenesis. C3H/HeJ (Tlr4(Lps-d)) mice, which possess a mutation in the TLR4 intracellular domain preventing TLR4 signaling, and strain-matched wild-type control (C3H/HeOuJ) mice were infected intracerebrally or intraperitoneally with various doses of scrapie inoculum. Incubation periods were significantly shortened in C3H/HeJ compared with C3H/HeOuJ mice, regardless of the route of infection or dose administered. At the clinical phase of disease, brain PrP(Sc) levels in the two strains of mice showed no significant differences by Western blotting. In addition, compared with macrophages from C3H/HeOuJ mice, those from C3H/HeJ mice were unresponsive to fibrillogenic PrP peptides (PrP residues 106 to 126 [PrP(106-126)] and PrP(118-135)) and the TLR4 agonist lipopolysaccharide but not to the TLR2 agonist zymosan, as measured by cytokine production. These data confirm that innate immune activation via TLR signaling interferes with scrapie infection. Furthermore, the results also suggest that the scrapie pathogen, or a component(s) thereof, is capable of stimulating an innate immune response that is active in the central nervous system, since C3H/HeJ mice, which lack the response, exhibit shortened incubation periods following both intraperitoneal and intracerebral infections.
authors: New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA. darylspinner@aol.com
authors: Daryl S
authors: DS
authors: Spinner
authors: In Soo
authors: IS
authors: Cho
authors: Seung Yong
authors: SY
authors: Park
authors: Jae Il
authors: JI
authors: Kim
authors: Harry C
authors: HC
authors: Meeker
authors: Xuemin
authors: X
authors: Ye
authors: Giuseppe
authors: G
authors: Lafauci
authors: Daniel J
authors: DJ
authors: Kerr
authors: Michael J
authors: MJ
authors: Flory
authors: Bo Sook
authors: BS
authors: Kim
authors: Regina B
authors: RB
authors: Kascsak
authors: Thomas
authors: T
authors: Wisniewski
authors: William R
authors: WR
authors: Levis
authors: Georgia B
authors: GB
authors: Schuller-Levis
authors: Richard I
authors: RI
authors: Carp
authors: Eunkyue
authors: E
authors: Park
authors: Richard J
authors: RJ
authors: Kascsak
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D005260:Female; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D017096:Prion Diseases / Q000276:immunology* / Q000503:physiopathology; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha