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EMBO reports 4, 2, 195–199 (2003)
doi:10.1038/sj.embor.embor731
Published online: 31 January 2003
Prion pathogenesis in the absence of Toll-like receptor signalling
Marco Prinz1, 3, Mathias Heikenwalder1, 3, Petra Schwarz1, Kiyoshi Takeda2, Shizuo Akira2 & Adriano Aguzzi1
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1 Institute of Neuropathology, University Hospital of Zürich, Schmelzbergstrasse 12, CH-8091 Zrich, Switzerland
2 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Osaka 565-0871, Japan
3 These authors contributed equally to this work
To whom correspondence should be addressed
Adriano Aguzzi Tel: +41 1 255 2107; Fax: +41 1 255 4402; adriano@pathol.unizh.ch
Received 18 September 2002; Accepted 21 November 2002; Published online 31 January 2003.
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Abstract
To reach the brain from peripheral sites, prions must colonize various cell types within the lymphoreticular compartment. However, no prion entry receptors are yet known. Toll-like receptors (TLRs) are pattern-recognition receptors that bind a multitude of pathogens and are therefore candidates as effectors of prion entry. Moreover, injection of unmethylated CpG oligodinucleotides, which stimulate TLR9, has been reported to delay peripherally initiated scrapie. We therefore studied prion infection in MyD88-/- mice, which are defective in TLR signalling. Despite subtle defects in splenic microarchitecture, MyD88-/- mice challenged intraperitoneally or intracerebrally were fully susceptible to disease and died of scrapie after similar incubation times to those of wild-type mice. Splenic infectivity titres rose to similar levels with the same kinetics, and brains showed similar histopathological changes. TLR signalling therefore does not have any major role in prion pathogenesis, and the protective effect of TLR stimulation is unlikely to result from direct interactions with prions.
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