Distinct transmissibility features of TSE sources derived from ruminant prion diseases by the oral route in a transgenic mouse model (TgOvPrP4) overexpressing the ovine prion protein.

Jean-Noël Arsac,Thierry Baron,Ina Maja Vorberg

doi:10.1371/journal.pone.0096215

Abstract

Transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative diseases associated with a misfolded form of host-encoded prion protein (PrP). Some of them, such as classical bovine spongiform encephalopathy in cattle (BSE), transmissible mink encephalopathy (TME), kuru and variant Creutzfeldt–Jakob disease in humans, are acquired by the oral route exposure to infected tissues. We investigated the possible transmission by the oral route of a panel of strains derived from ruminant prion diseases in a transgenic mouse model (TgOvPrP4) overexpressing the ovine prion protein (A136R154Q171) under the control of the neuron-specific enolase promoter. Sources derived from Nor98, CH1641 or 87V scrapie sources, as well as sources derived from L-type BSE or cattle-passaged TME, failed to transmit by the oral route, whereas those derived from classical BSE and classical scrapie were successfully transmitted. Apart from a possible effect of passage history of the TSE agent in the inocula, this implied the occurrence of subtle molecular changes in the protease-resistant prion protein (PrPres) following oral transmission that can raises concerns about our ability to correctly identify sheep that might be orally infected by the BSE agent in the field. Our results provide proof of principle that transgenic mouse models can be used to examine the transmissibility of TSE agents by the oral route, providing novel insights regarding the pathogenesis of prion diseases.

Highlights

Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases that affect both humans and animals
Inocula were derived from i) natural cases of classical bovine spongiform encephalopathy (BSE) in cattle and classical scrapie in sheep [23], ii) atypical natural TSE isolates collected by active surveillance of scrapie (‘‘CH1641 like’’, Nor98) [16,24] or of BSE (L-type BSE) [18], iii) experimental samples including classical BSE and CH1641 in AA136RR154QQ171 sheep [16,25], transmissible mink encephalopathy (TME) in cattle [18] or scrapie strains passaged in wildtype mice (87V, C506M3) [17]
We examined the transmissibility by the oral route of ten TSE sources from cattle or sheep previously described in the TgOvPrP4 transgenic mouse model, after two serial passages by the intracerebral route in this mouse line

Summary

Introduction

Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases that affect both humans and animals. Typical features include characteristic spongiform changes in the brain associated with neuron loss, an absence of inflammatory response, and accumulation in the brain, and sometimes in lymphoid tissues, of an abnormal, partially protease-resistant (PrPres) form of the neuronal prion protein (PrP) encoded by the prnp gene of the host [1] This disease-associated protein is associated with transmissibility of the disease. As a result of increased surveillance in the past years, atypical and/or rare TSEs have been identified in cattle (H-type and L-type BSEs) and in small ruminants (Nor and scrapie isolates reminiscent of CH1641 experimental scrapie) [7,8,9,10] The origins of these TSEs remain debated but at least some of them (H-type and L-type BSEs, Nor98) probably arise sporadically [10,11], such as most cases of Creutzfeldt-Jakob disease (CJD) in humans [12], particular sequences of the prnp gene (A136H154Q171 and A136F141R154Q171 genotypes) have a major predisposing influence in the case of No98 [13]

Methods

Results

Conclusion