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Journal of Virology, November 2008, p. 10701-10708, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00522-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Accelerated Prion Disease Pathogenesis in Toll-Like Receptor 4 Signaling-Mutant Mice{triangledown}

Daryl S. Spinner,1* In Soo Cho,2 Seung Yong Park,3 Jae Il Kim,1,{dagger} Harry C. Meeker,1 Xuemin Ye,1,{ddagger} Giuseppe LaFauci,1 Daniel J. Kerr,1 Michael J. Flory,1 Bo Sook Kim,4 Regina B. Kascsak,1 Thomas Wisniewski,1,5 William R. Levis,5 Georgia B. Schuller-Levis,1 Richard I. Carp,1 Eunkyue Park,1 and Richard J. Kascsak1*

New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York 10314,1 National Veterinary Research and Quarantine Service, Anyang, Gyunggi-do 430-824, Republic of Korea,2 College of Veterinary Medicine, Konkuk University, Seoul 143-701, Republic of Korea,3 Seoul Grand Park Zoo, Gwacheon, Gyunggi-do 427-702, Republic of Korea,4 New York University School of Medicine, 550 First Avenue, New York, New York 100165

Received 8 March 2008/ Accepted 21 April 2008

Prion diseases such as scrapie involve the accumulation of disease-specific prion protein, PrPSc, 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 (Tlr4Lps-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 PrPSc 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 [PrP106-126] and PrP118-135) 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.

* Corresponding author. Mailing address: New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314. Phone for D. S. Spinner: (718) 494-5148. Fax: (718) 698-0896. E-mail: darylspinner{at}aol.com. Phone for R. J. Kascsak: (718) 494-5147. Fax: (718) 698-1553. E-mail: rrkascsak{at}msn.com

{triangledown} Published ahead of print on 20 August 2008.

{dagger} Present Address: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44120.

{ddagger} Present Address: Department of Ophthalmology, Mount Sinai School of Medicine, New York, NY 10029.

Journal of Virology, November 2008, p. 10701-10708, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00522-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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