The risk of the transmission of ruminant transmissible spongiform encephalopathy (TSE) to humans was thought to be low due to the lack of association between sheep scrapie and the incidence of human TSE. However, a single TSE agent strain has been shown to cause both bovine spongiform encephalopathy (BSE) and human vCJD, indicating that some ruminant TSEs are transmissible to humans. While the transmission of cattle BSE to humans in transgenic mouse models has been inefficient, indicating the presence of a significant transmission barrier between cattle and humans, BSE has been transmitted to a number of other species. Here, we aimed to further investigate the human transmission barrier following the passage of BSE in a sheep. Following inoculation with cattle BSE, gene-targeted transgenic mice expressing human PrP showed no clinical or pathological signs of TSE disease. However, following inoculation with an isolate of BSE that had been passaged through a sheep, TSE-associated vacuolation and proteinase K-resistant PrP deposition were observed in mice homozygous for the codon 129-methionine PRNP gene. This observation may be due to higher titers of the BSE agent in sheep or an increased susceptibility of humans to BSE prions following passage through a sheep. However, these data confirm that, contrary to previous predictions, it is possible that a sheep prion is transmissible to humans and that BSE from other species is a public health risk.The transmissible spongiform encephalopathies (TSEs) are a group of fatal infectious neurodegenerative diseases that include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeldt-Jakob disease (CJD) in humans. TSEs are characterized by the accumulation in the brain of PrP Sc , which is a conformational variant of the normal cellular host prion protein (PrP C ). The abnormal form of the protein is protease resistant and detergent insoluble, and it aggregates in diffuse or amyloid deposits in the central nervous system (CNS) and lymphoreticular system of infected animals. TSEs are infectious diseases and can be transmitted between animals of the same and different species by a number of routes, including oral, environmental, or iatrogenic exposure. The host range is a specific characteristic of each strain, but TSE agents usually transmit more readily within rather than between species. Low transmission rates often are observed upon transmission to a new species, but on further passage in the new species increased transmission rates and shorter incubation times usually are observed. This effect is referred to as the species barrier. The ability of individual TSE agents to cross a species barrier can be examined experimentally by the direct inoculation of different species or modeled in transgenic mice expressing PrP sequences from these species. Modeling species barriers in mice is particularly important when assessing the risks of infection in humans. Such experiments can assess risk posed by different TSE agents and also the potential for the mu...

Bovine spongiform encephalopathy (BSE) in cattle and variant Creutzfeldt–Jakob disease in humans have previously been shown to be caused by the same strain of transmissible spongiform encephalopathy agent. It is hypothesized that the agent spread to humans following consumption of food products prepared from infected cattle. Despite evidence supporting zoonotic transmission, mouse models expressing human prion protein (HuTg) have consistently shown poor transmission rates when inoculated with cattle BSE. Higher rates of transmission have however been observed when these mice are exposed to BSE that has been experimentally transmitted through sheep or goats, indicating that humans may potentially be more susceptible to BSE from small ruminants. Here we demonstrate that increased transmissibility of small ruminant BSE to HuTg mice was not due to replication of higher levels of infectivity in sheep brain tissue, and is instead due to other specific changes in the infectious agent.

I n 2016, a definite case of clinical variant Creutzfeldt-Jakob disease (vCJD) in a person heterozygous for methionine/valine (MV) at codon 129 of the prion protein gene (PRNP 129MV) was reported in the United Kingdom (1). Given the relatively atypical clinical features in this case, we considered it important to ascertain the strain of prion agent to determine whether there had been strain adaption or whether the patient's genetic background may have influenced the disease phenotype. We conducted a study to determine whether we could isolate the same prion strain from this case of vCJD in a 129MV individual as was identified in previous 129 methionine homozygous (129MM) genotype vCJD cases, consistent with the hypothesis of a causal link to bovine spongiform encephalopathy (BSE). The clinical features for this patient were consistent with a diagnosis of either vCJD or sporadic Creutzfeldt-Jakob disease (sCJD). Results from magnetic resonance imaging (MRI) of the patient's brain were suggestive of sCJD on diffusion-weighted imaging (DWI) sequences, although the single coronal fluid-attenuated inversion recovery (FLAIR) sequence in this case was not diagnostic because of movement artifact. Results of cerebrospinal fluid (CSF) real-time quaking-induced conversion assay analysis and the direct detection assay for vCJD infection in the blood were negative. However, at autopsy, neuropathological examination revealed florid plaques, and biochemical analysis of prion protein (PrP) from the brain confirmed a type 2B profile, both characteristic of vCJD (1). Abnormal PrP was also detected in peripheral tissues. Recent studies in which researchers used protein misfolding cyclic amplification in CSF were positive in this case of vCJD, but not in sCJD cases, including those with a heterozygous genotype (2). The Study We injected 18 RIII mice with 10% wt/vol frozen central nervous system tissue, 0.02 mL intracerebrally and 0.1 mL intraperitoneally, from a 129MV patient with a clinical case of vCJD (1). The vCJD tissue samples were provided by the NHS National Prion Clinic, University College London (UCL) Hospitals (London, UK), and MRC Prion Unit at UCL and sourced through the MRC Edinburgh Brain Bank (Edinburgh, Scotland, UK). The Brain Bank has full ethics approval and consent for the use of tissue in research (East of Scotland Research Ethics Service, Ref 16/ES/0084) and works within the framework of the Human Tissue (Scotland) Act 2006. We conducted inoculation, clinical scoring, and neuropathological and biochemical analysis of the mice as previously described (3-5). Animal studies were conducted according to the regulations of the UK Home Office Animals (Scientific Procedures) Act 1986. The isolate from the brain of the 129MV patient transmitted successfully; clinical and neuropathological signs associated with prion disease appeared in the mice. We compared the mean incubation period, neuropathological signs, and biochemical analysis with archived records of UK 129MM vCJD central nervous system transmissions and UK BSE...