Search

Summary: The prion protein gene (Prnp) plays a crucial role in the susceptibility of sheep to scrapie in terms of attack rate and/or incubation period. However, the influence of Prnp on the pathogenesis of the disease, specifically the involvement of tissues of the lymphoreticular system (LRS), pathways of neuroinvasion and neuropathological phenotypes, remains controversial. This study reports the onset and progression of disease-associated prion protein (PrPd) accumulation in the LRS and nervous tissues of sheep of six different Prnp genotypes infected by oral administration of the same mixed scrapie brain homogenate. Sheep homozygous for glutamine (Q) at codon 171 of PrP, with either valine (V) or alanine (A) at codon 136 (i.e. VRQ/VRQ, VRQ/ARQ and ARQ/ARQ), showed early and consistent PrPd accumulation in LRS tissues of the pharynx and gut. In contrast, LRS involvement was minimal, inconsistent and occurred late in the incubation period in sheep heterozygous for arginine (R) at codon 171 (i.e. VRQ/ARR and ARQ/ARR). Despite this difference, all five groups were susceptible to infection and developed clinical disease, albeit with significantly different incubation periods (shortest in VRQ/VRQ and longest in ARQ/ARR sheep). The remaining group of ARR/ARR homozygous sheep did not show evidence of infection at the end of the experiment or at previous predetermined time points. As for LRS tissues, the sites of initial PrPd accumulation in the brain were determined immunohistochemically. These were the same in all susceptible sheep (except for ARR/ARR sheep), regardless of their Prnp genotype which, together with an early and consistent accumulation of PrPd in circumventricular organs and a late or inconsistent involvement of the enteric and autonomic nervous system and of the spinal cord, suggests neuroinvasion occurring via the blood. The neuropathological phenotype (PrPd profile in the central nervous system) of clinically affected sheep was similar in the three V136 carrier groups, but showed some differences in the two A136 homozygous groups, suggesting a codon 136-driven selection of different strains from the mixture contained in the inoculum. ARQ/ARR sheep showed an irregular distribution of brain PrPd, contrasting with the more widespread distribution of the other four groups. The results indicate that (1) ARQ/ARR sheep are more susceptible to oral scrapie infection than would be predicted from incidence figures in natural disease, (2) amplification and accumulation of PrPd in LRS tissues is host genotype dependent, but does not necessarily have a marked effect on the outcome of the infection and (3) the neuropathological phenotype of scrapie is related to the host genotype, but possibly in combination with the infecting source. [ABSTRACT FROM AUTHOR]

Summary: The pathogenesis of scrapie in sheep after natural or oral exposure to the infectious agent generally involves the early accumulation of disease-associated prion protein (PrPd) in the lymphoreticular system (LRS). This phase is followed by neuroinvasion, for which two routes, ascending neural and haematogenous, have been postulated. The present study reports the use of immunohistochemistry to track the tissue progression of PrPd deposition in sheep of a single, highly scrapie-susceptible PrP genotype administered by the oral or conjunctival routes. Regardless of the route of infection, the earliest detection of PrPd was in gut- and pharynx-associated LRS tissues. Subsequently, the brain became PrPd positive simultaneously with other LRS tissues, but before the spinal cord and peripheral nervous tissues of the enteric, parasympathetic and sympathetic systems. The sites of initial PrPd accumulation in the brain were the dorsal motor nucleus of the vagus and the hypothalamus and their related circumventricular organs (the area postrema and the median eminence, respectively). These were the same for both routes of infection. Rapid progression to clinical disease was observed in sheep infected orally or conjunctivally, with definite signs of scrapie recorded at around 6 and 8 months after infection, respectively. Longer incubation periods in sheep infected by the conjunctival route were probably due to them receiving a lower dose than those infected orally. Irrespective of the route of infection, clinically affected sheep showed the same pathological phenotype (PrPd profile) and PrPd distribution throughout the brain. The identical peripheral and central pathogenesis observed in sheep of both groups suggests early dissemination of the infectious agent in the bloodstream and a common neuroinvasion pathway. The late involvement of the enteric and autonomic nervous system supports a haematogenous route of infection to the brain. [ABSTRACT FROM AUTHOR]

Summary: Neuroinflammation elicited by PrPres (resistant prion protein [PrP]) deposits in the central nervous system (CNS) has been shown to involve cellular and oxidative stress responses in bovine spongiform encephalopathy (BSE) as well as in several murine models of transmissible spongiform encephalopathy (TSE). Additionally, deregulation of water homeostasis has been suggested to be a further component of the spongiform changes observed in TSEs. The aim of the present study was to characterize the pathogenic events occurring in the CNS of sheep with spontaneously arising classical scrapie. Brains from seven affected animals and two controls were subject to immunohistochemical and histochemical examinations. Semi-quantitative evaluation of PrPres deposits and spongiform changes throughout the encephalon confirmed that PrPres deposition elicits significant astroglial and microglial reactions, as evidenced by an increase in the number of glial cells and changes in glial cell morphology involving increased expression of vimentin. The altered expression of metallothionein and heat shock protein 25 (HSP25) suggested that this neuroinflammatory reaction entails cellular and oxidative stress responses. In contrast, there was no change in expression of the membrane-associated water channel aquaporin 1 when PrPres accumulated in the brain. [Copyright &y& Elsevier]