Résumé des résultats (Abstract)
(Anglais)
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The transmission of BSE to humans and the occurrence of nvCJD represent international emergencies. However, the peak of BSE incidence has occurred many years ago, and highly effective measures have been long put in place to minimize cattle-born risks to humans. However, the possibility has to be considered that humans may have contracted subclinicalor pre-clinical nvCJD, and may act as reservoirs for human-to-human transmission.
In this framework, the main goal of the present proposal is the:
1) assessment of risks presented by blood and blood products. It is imperative to use an experimental model as close to humans as possible, and will therefore resort to rhesus monkeys (M. mulatta). In addition, the proposed study will;
2) further the understanding of nvCJD pathogenesis, andalso yield a rational basis for;
3) secondary prophylaxis of nvCJD after infection.
%SPECIFIC GOALS:
- To determine the affinity of the nvCJD and BSE agents for Iymphoid tissue in non-human primates;
- To identify the cell types within the Iymphoid tissue of primates which sustain prion replication;
- To assess whether prions enter the blood circulation;
- To validate presymptomatic tonsil biopsy assays for infectivity, and to asses the time lag between infection and tonsil positively, and between tonsil positivity and neurological disease.
EXPERIMENTAL DESIGN:
1. Sequencing of the macaque Prnp open reading frame (ORF);
2. Construction of macaque transgenic mice susceptible to macaque BSE and CJD;
3. Peripheral inoculation of rhesus macaque (M. mulata) with BSE and nvCJD. InonvCJD, sCJD (titrated in mice and squirrel monkeys) and BSE inoculum (cow-titrated) as control inoculum;
4. Distribution of infectivity in blood and Iymphoid tissue;
5. Infectivity bioassay in humanized MeVMet transgenic mice, chimeric macaquemice and wild type mice.
BIOSAFETY CONSIDERATION: Primary inoculation and infectivity bioassays will be carried out in a Biosafet Level 4 unit (P4) of the Hans Popper Primate Center of Immuno AG, Orth a/Donau,Austria. Biochemical and histological analysis will be performed in a P3 laborat the Institute of Neuropathology/Zurich, bioassays in a P3 facility at the Imperial College, London.
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