Isolation from Cattle of a Prion Strain Distinct from That Causing Bovine Spongiform Encephalopathy

Abstract

To date, bovine spongiform encephalopathy (BSE) and its human counterpart, variant Creutzfeldt-Jakob disease, have been associated with a single prion strain. This strain is characterised by a unique and remarkably stable biochemical profile of abnormal protease-resistant prion protein (PrP^res) isolated from brains of affected animals or humans. However, alternate PrP^res signatures in cattle have recently been discovered through large-scale screening. To test whether these also represent separate prion strains, we inoculated French cattle isolates characterised by a PrP^res of higher apparent molecular mass—called H-type—into transgenic mice expressing bovine or ovine PrP. All mice developed neurological symptoms and succumbed to these isolates, showing that these represent a novel strain of infectious prions. Importantly, this agent exhibited strain-specific features clearly distinct from that of BSE agent inoculated to the same mice, which were retained on further passage. Moreover, it also differed from all sheep scrapie isolates passaged so far in ovine PrP-expressing mice. Our findings therefore raise the possibility that either various prion strains may exist in cattle, or that the BSE agent has undergone divergent evolution in some animals. Prions are unconventional agents of proteic nature that are formed of abnormal conformations of the host-encoded prion protein (PrP). They cause fatal neurodegenerative diseases in both animals and humans, and can be transmitted between species as exemplified in humans by the emergence of variant Creutzfeldt-Jakob disease following the epidemic of bovine spongiform encephalopathy (BSE) in the United Kingdom. Since diagnosis of prion infection is only possible once the central nervous system has been invaded, brains of slaughtered or fallen cattle are routinely screened in Europe to protect the consumers from BSE. This has unexpectedly led to the discovery of unprecedented PrP conformations that were distinct from the single one associated so far with BSE or BSE-related diseases. To precisely determine their etiology, the authors have studied the transmissibility of these new conformations, termed H-type, to transgenic mice expressing either bovine or ovine PrP. They show that these cases are highly pathogenic for these mice. The authors also demonstrate that they are not directly related to the agent involved in the BSE epidemic, supporting the view for isolation of a new prion strain from cattle, whose prevalence and associated zoonotic risk should be carefully monitored in the future.