Phenotype of disease-associated PrP accumulation in the brain of bovine spongiform encephalopathy experimentally infected sheep

Abstract

In view of the established link between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt–Jakob disease and of the susceptibility of sheep to experimental BSE, the detection of potential cases of naturally occurring BSE in sheep has become of great importance. In this study, the immunohistochemical (IHC) phenotype of disease-associated prion protein (PrPd) accumulation has been determined in the brain of 64 sheep, of various breeds and PrP genotypes, that had developed neurological disease after experimental BSE challenge with different inocula by a range of routes. Sheep BSE was characterized by neuron-associated intra- and extracellular PrPd aggregates and by conspicuous and consistent deposits in the cytoplasm of microglia-like cells. The stellate PrPd type was also prominent in most brain areas and marked linear deposits in the striatum and midbrain were distinctive. Sheep of the ARR/ARR and ARQ/AHQ genotypes displayed lower levels of PrPd than other sheep, and intracerebral BSE challenge resulted in higher levels of PrPd accumulating in the brain compared with other routes. The PrP genotype and the route of challenge also appeared to affect the incubation period of the disease, giving rise to complex combinations of magnitude of PrPd accumulation and incubation period. Despite these differences, the phenotype of PrPd accumulation was found to be very consistent across the different factors tested (notably after subpassage of BSE in sheep), thus highlighting the importance of detailed IHC examination of the brain of clinically affected sheep for the identification of potential naturally occurring ovine BSE.

Disease phenotype in sheep after infection with cloned murine scrapie strains

“…Similarly, 79A combined challenge VRQ/VRQ (2/2) Cheviot sheep developed terminal disease at 671 and 743 dpi activation and abnormal neuromodulary responses at clinical stages of the disease. 2 The significance of different lesions in TSEs can be difficult to establish as they may vary markedly from case to case depending on the source (strain), [3][4][5][6] or on host factors like the Prnp genotype. [7][8][9] Vacuolar lesion profiles in sheep 7,10 were insufficiently reproducible when individuals experimentally challenged with a single scrapie isolate were compared.…”

“…The full [3][4][5] 12 The epitope mapping approach using immunohistochemistry (IHC) revealed differences between strains like BSE and CH1641 in comparison with scrapie. 13 Experimentally, scrapie can be transmitted to a number of species, including livestock and laboratory animals.…”

Early and Rapid Engraftment of Bone Marrow-Derived Microglia in Scrapie

“…Depending on the agent strainhost combination, microglial activation can precede or follow the accumulation of pathological prion protein (Baker et al, 1999). Perivascular macrophages and microglia express PrP C in vivo (Esiri et al, 2002), and PrP Sc was detected in microglia from Kuru-, CJD-, BSE-, and scrapie-affected brains (Miyazono et al, 1991;Guiroy et al, 1994;Andréoletti et al, 2002a;González et al, 2005;Kovács et al, 2005).…”

Quantifying the risk from ovine BSE and the impact of control strategies

“…While infectivity in cattle is largely confined to the nervous system ( Wells et al 1998), the same is not true for sheep. BSE infectivity and disease-associated prion protein have been found to be widespread throughout the body of an infected sheep ( Foster et al 2001b;Jeffrey et al 2001;Ferguson et al 2002;Bellworthy et al 2005b;Gonzalez et al 2005), even in the early stages of infection. Furthermore, a number of tissues that have been shown to carry infectivity are currently eaten by humans and cannot be completely removed from a sheep carcass.…”

“…We also quantify the probable impact of a range of control options. This study collates data from a wide range of sources, including the 2002 anonymous scrapie postal survey (Sivam et al 2003(Sivam et al , 2006 and the Institute for Animal Health (IAH) farm-based scrapie flock survey (Baylis et al 2000), and published data on studies of natural scrapie (Hadlow et al 1982;Andreoletti et al 2000;van Keulen et al , 2002 and experimental BSE ( Foster et al 2001b;Jeffrey et al 2001;Ferguson et al 2002;Houston et al 2003;Bellworthy et al 2005b;Gonzalez et al 2005). These data are used to parametrize a mathematical model that tracks rising infectivity within infected sheep, sheep-to-sheep transmission within a flock and the rate at which sheep leave flocks to enter the food chain.…”