Atypical transmissible spongiform encephalopathies (TSEs) in ruminants

Abstract

Transmissible spongiform encephalopathies (TSEs) are associated with the accumulation in infected tissues of a disease-associated form of a host-encoded protein, the prion protein (PrP). Contrary to the normal form of the protein, this form of PrP is partially resistant to protease digestion (PrP^res). Detailed characterisation of PrP^res has been intensively investigated in recent years to try and decipher the diversity of TSEs in human and animals. This considerably and unexpectedly enlarged our knowledge about such diseases in ruminants. Previously, such a diversity was essentially shown by the demonstration that scrapie from sheep and goats could have different biological behaviours following transmission of the disease in mice, unlike bovine spongiform encephalopathy from cattle (BSE) which showed a distinct and unique behaviour. The properties of the BSE agent were also demonstrated to be very stable, following transmission to a variety of different species. Molecular studies of PrP^res, followed by transmission studies to mice, gave the first evidence for the accidental transmission of the BSE agent to humans where it induced a variant form of the fatal Creutzfeldt-Jakob disease (CJD) and also to different animal species including a goat in France. This last case was found among a few unusual cases of TSEs in small ruminants that showed some molecular similarities with BSE and which are currently under investigation by transmission studies in mice. The application of the molecular methods to characterise PrP^res has most recently led to the unexpected discovery of deviant BSE forms in a few affected cattle in Europe and in the United States, which raises the question of a possible different origin at least of some cases of BSE in cattle. Finally, considerable numbers of a new TSE form in small ruminants, referred to as “atypical scrapie” or “Nor98”, have meanwhile been identified in most European countries by TSE rapid testing using an assay which recognizes also comparatively less PK resistant PrP^res.

Introduction

Transmissible spongiform encephalopathies (TSEs) are fatal neuro-degenerative diseases, affecting both human (Creutzfeldt-Jakob disease; CJD) and animals, including mainly sheep and goats (scrapie), deer and elk (chronic wasting disease; CWD) and cattle (bovine spongiform encephalopathy; BSE). The exact nature of the infectious agent involved in the transmission of these diseases remains controversial. However, a central event in their pathogenesis is the accumulation in infected tissues of an abnormal form of a host-encoded protein, the prion protein (PrP) [1], [2]. Whereas the normal cellular protein is fully sensitive to proteases (PrP^sen), the disease-associated prion protein (PrP^d) is only partly degraded (PrP^res), its amino-terminal end being removed.

Experimental transmissions of these diseases, especially that of scrapie from small ruminants, revealed a biological diversity of the involved infectious agent, reminiscent of “strains” among classical infectious agents, like viruses [3]. This has been mainly described in genetically defined inbred wild-type mice, by the different features of the disease between different strains, including differences in the incubation periods and in the distribution of brain lesions; these features remained generally remarkably stable following serial passages of a given strain in a given mouse model [4], [5].

Distinct and specific features of the PrP^res protein, as characterised in most studies by Western blot methods, have also been found in mice or in hamsters infected with different biological strains of TSE agents, suggesting that biological properties of the infectious agent might be enciphered in the conformation of the disease-associated form of the prion protein [6], [7], [8], [9], [10], [11], [12].