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From: TSS ()
Date: March 5, 2007 at 10:23 am PST

Bovine Spongiform Encephalopathy Agent in a Prion Protein (PrP)ARR/ARR Genotype Sheep after Peripheral Challenge: Complete Immunohistochemical Analysis of Disease-Associated PrP and Transmission Studies to Ovine-Transgenic Mice

Anna Bencsik and Thierry Baron

Agence Française de Sécurité Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels, Lyon, France

(See the article by Crozet et al., on pages 997–1006.)

Possible transmission of the bovine spongiform encephalopathy (BSE) agent to ovine species has been considered for several years. It has been recently demonstrated that the BSE agent, after intracerebral challenge, can infect sheep believed to be the most resistant genetically to prion diseases (prion protein [PrP]ARR/ARR genotype). We report here the results of a detailed immunohistochemical analysis of the disease-associated PrP (PrPd) in all organs from a PrPARR/ARR sheep infected with the BSE agent by a peripheral route. Because PrPd was detected in the brain in the absence of any clinical symptoms, transmission studies were also performed using a sensitive ovine-transgenic mouse model—Tg(OvPrP4)—that can identify the BSE agent on the basis of the occurrence of florid plaques in the mouse brain. The data indicated that these PrPd deposits were linked to the BSE agent and were associated with infectivity. This suggests that PrPARR/ARR sheep may be silent carriers of the BSE agent.


Received 29 August 2006; accepted 2 October 2006; electronically published 16 February 2007.
Potential conflicts of interest: none reported.
Financial support: "Programme National de Recherches sur les ESST et les Prions" Groupement d'Intérêt Scientifique "Infections à Prions."

Peripheral Circulation of the Prion Infectious Agent in Transgenic Mice Expressing the Ovine Prion Protein Gene in Neurons Only

Carole Crozet,1,a Stéphane Lezmi,1 Frédéric Flamant,2 Jacques Samarut,2 Thierry Baron,1 and Anna Bencsik1

1Agence Française de Sécurité Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels, and 2Ecole Normale Supérieure de Lyon, Laboratoire de Biologie Moléculaire et Cellulaire, Institut Fédératif de Recherche 128, Biosciences Lyon-Gerland, Lyon, France

(See the article by Bencsik and Baron, on pages 989–96.)

Background. For prion diseases, even if a large body of evidence indicates that both the lymphoreticular system (LRS) and peripheral nerves are involved in scrapie neuroinvasion, the processes by which prions invade the central nervous system are only partially understood.
Methods. Transgenic Tg(OvPrP4) mice, which express the ovine prion protein (PrP) gene under the rat neuron–specific enolase promoter on a knockout background, were used to study prion extracerebral circulation after scrapie prions were inoculated via the intracerebral (ic) and the intraperitoneal (ip) route.
Results. Surprisingly, PrPSc was detected in the spleens of mice inoculated ic with prions. Moreover, the absence of the ovine PrPC in nonneural tissue at the periphery did not stop neuroinvasion after ip challenge. Additionally, pilot studies performed in Tg(OvPrP4) mice that had undergone splenectomy before ic prion inoculation showed that the time course of the disease is delayed.
Conclusions. Given that these mice express the ovine PrP gene in neuronal cells but not in nonnervous tissue, our results suggest that PrPC expressed by cells of the LRS are not necessary for neuroinvasion or for their ability to accumulate PrPSc and emphasize the importance of extracerebral circulation of PrPC or PrPSc for the development of the disease.


Received 16 August 2006; accepted 2 November 2006; electronically published 16 February 2007.
Potential conflicts of interest: none reported.
Presented in part: Keystone Symposia: Molecular Aspects of Transmissible Spongiform Encephalopathies (Prion Diseases), Breckenridge, Colorado, 2–6 April 2003 (abstract 123).
Financial support: La Fondation pour la Recherche Médicale (grant to C.C.).
a Present affiliation: Institut de Génétique Humaine, UPR1142 Centre National de la Recherche Scientifique, Montpellier, France.


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