Increased Susceptibility of Human-PrP Transgenic Mice to Bovine Spongiform Encephalopathy Infection following Passage in Sheep

Abstract

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...

Les prions, agents d’encéphalopathies transmissibles chez les mammifères

“…Un degré supplémentaire de complexité est apporté par la séquence en acides aminés / structure de la PrP C de l'hôte sur laquelle la souche de prion s'est initialement répliquée avant le transfert inter-espèces. Les prions associés à l'ESB classique sont par exemple plus virulents pour des modèles de souris transgéniques pour la PrP humaine lorsqu'ils proviennent du mouton ou de la chèvre (naturellement ou expérimentalement infectés, figure 1) que lorsqu'ils proviennent directement de la vache (Padilla et al, 2011, Plinston et al, 2011.…”

Dissociation of Prion Protein Amyloid Seeding from Transmission of a Spongiform Encephalopathy

“…PrP immunoblotting. Brain tissues from terminally ill GSS-22 and asymptomatic 101LL mice (used for subpassage) were digested with proteinase K (PK) (20 g/ml), incubated at 37°C for 1 h, and prepared for immunoblotting as described previously (26). Brain tissues from 129/Ola mice inoculated with strain ME7 of mouse-adapted TSE (scrapie) and from uninoculated 101LL mice were processed in the same way as controls.…”

Scientific Opinion on a request for a review of a scientific publication concerning the zoonotic potential of ovine scrapie prions

“…Interestingly, despite their lack of susceptibility to cattle BSE, HuMM transgenic mice were partially susceptible to sheep-passaged and goat-passaged BSE prions (Plinston et al, 2011(Plinston et al, , 2014Wilson et al, 2013).…”

“…In addition, these gene-targeted transgenic mouse lines were challenged with two natural sheep scrapie isolates (Plinston et al, 2011) and two natural goat scrapie isolates (Wilson et al, 2013). Limited information on the strain properties of sheep isolates was available.…”