Role of PrP in prion spread and establishment of central nervous system infection

• Research unit: EU RFP
• Project number: 98.0185

Key words (English)

Prions; BSE; Creutzfeldt-Jakob

Alternative project number (English)

EU project number: FAIRJ-CT98-6022

Research programs (English)

EU-programme: 4. Frame Research Programme - 4.3 Biomedical/Health research

Short description (English)

See abstract

Partners and International Organizations (English)

Coordinator: Commissariat ä l'Energie Atomique, Fontenay (F)

Abstract (English)

Prion pathogenesis after intraperitoneal challenge requires intact lymphoreticular organs. Analogously, oral pathogenesis is thought to involve gut-associated lymphatic tissue, which includes Peyer's patches (PPs) and M cells. Homing of activated B lymphocytes to PPs requires a4b7 integrin: PPs of b7?/? mice are normal in number, yet atrophic and almost devoid of B cells. Here we studied oral prion pathogenesis in b7?/? mice. Minimal infectious dose, and disease incubation after exposure to logarithmic prion dilutions, were similar in b7?/? and wild-type mice. Although oral LD50 was 4 log higher than intraperitoneal LD50 in both genotypes, PPs of both b7?/? and wild-type mice contained 3-4 logLD50/g prion infectivity >125 days after challenge. Despite strongly depleted B cells, M cells were still present in b7?/? mice. Instead, mice deficient in tumor necrosis factor and lymphotoxin-a (TNFa?/? x LTa?/?) or in lymphocytes (RAG?1?/?, µMT), whose PPs were reduced in number, were highly resistant to oral challenge, and their intestine was virtually devoid of prion infectivity at all times after challenge. Therefore lymphoreticular requirements for enteric and for intraperitoneal uptake of prions are dramatically different from each other. Susceptibility to prion infection after oral challenge correlates with the number of PPs, but is independent of their proper equipment with lymphocytes.

References in databases (English)

Swiss Database: Euro-DB of the
State Secretariat for Education and Research
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CH-3003 Berne, Switzerland
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Swiss Project-Number: 98.0185