Bovine adapted transmissible mink encephalopathy is similar to L-BSE after passage through sheep with the VRQ/VRQ genotype but not VRQ/ARQ.

BACKGROUND: Transmissible mink encephalopathy (TME) is a fatal neurologic disease of farmed mink. Evidence indicates that TME and L-BSE are similar and may be linked in some outbreaks of TME. We previously transmitted bovine adapted TME (bTME) to sheep. The present study compared ovine passaged bTME (o-bTME) to C-BSE and L-BSE in transgenic mice expressing wild type bovine prion protein (TgBovXV). To directly compare the transmission efficiency of all prion strains in this study, we considered the attack rates and mean incubation periods. Additional methods for strain comparison were utilized including lesion profiles, fibril stability, and western blotting. RESULTS: Sheep donor genotype elicited variable disease phenotypes in bovinized mice. Inoculum derived from a sheep with the VRQ/VRQ genotype (o-bTMEVV) resulted in an attack rate, incubation period, western blot profile, and neuropathology most similar to bTME and L-BSE. Conversely, donor material from a sheep with the VRQ/ARQ genotype (o-bTMEAV) elicited a phenotype distinct from o-bTMEVV, bTME and L-BSE. The TSE with the highest transmission efficiency in bovinized mice was L-BSE. The tendency to efficiently transmit to TgBovXV mice decreased in the order bTME, C-BSE, o-bTMEVV, and o-bTMEAV. The transmission efficiency of L-BSE was approximately 1.3 times higher than o-bTMEVV and 3.2 times higher than o-bTMEAV. CONCLUSIONS: Our findings provide insight on how sheep host genotype modulates strain genesis and influences interspecies transmission characteristics. Given that the transmission efficiencies of L-BSE and bTME are higher than C-BSE, coupled with previous reports of L-BSE transmission to mice expressing the human prion protein, continued monitoring for atypical BSE is advisable in order to prevent occurrences of interspecies transmission that may affect humans or other species.

Oral Transmission of L-Type Bovine Spongiform Encephalopathy Agent among Cattle.

To determine oral transmissibility of the L-type bovine spongiform encephalopathy (BSE) prion, we orally inoculated 16 calves with brain homogenates of the agent. Only 1 animal, given a high dose, showed signs and died at 88 months. These results suggest low risk for oral transmission of the L-BSE agent among cattle.

L-type bovine spongiform encephalopathy in genetically susceptible and resistant sheep: changes in prion strain or phenotypic plasticity of the disease-associated prion protein?

BACKGROUND: Sheep with prion protein (PrP) gene polymorphisms QQ171 and RQ171 were shown to be susceptible to the prion causing L-type bovine spongiform encephalopathy (L-BSE), although RQ171 sheep specifically propagated a distinctive prion molecular phenotype in their brains, characterized by a high molecular mass protease-resistant PrP fragment (HMM PrPres), distinct from L-BSE in QQ171 sheep. METHODS: The resulting infectious and biological properties of QQ171 and RQ171 ovine L-BSE prions were investigated in transgenic mice expressing either bovine or ovine PrP. RESULTS: In both mouse lines, ovine L-BSE transmitted similarly to cattle-derived L-BSE, with respect to survival periods, histopathology, and biochemical features of PrPres in the brain, as well as splenotropism, clearly differing from ovine classic BSE or from scrapie strain CH1641. Nevertheless and unexpectedly, HMM PrPres was found in the spleen of ovine PrP transgenic mice infected with L-BSE from RQ171 sheep at first passage, reminiscent, in lymphoid tissues only, of the distinct PrPres features found in RQ171 sheep brains. CONCLUSIONS: The L-BSE agent differs from both ovine classic BSE or CH1641 scrapie maintaining its specific strain properties after passage in sheep, although striking PrPres molecular changes could be found in RQ171 sheep and in the spleen of ovine PrP transgenic mice.

RT-QuIC detection of pathological prion protein in subclinical goats following experimental oral transmission of L-type BSE.

OBJECTIVE: The spread of bovine spongiform encephalopathy (BSE) agent to small ruminants is still a major issue in the surveillance of transmissible spongiform encephalopathies (TSEs). L-type bovine spongiform encephalopathy (L-BSE) is an atypical form of BSE with an unknown zoonotic potential that is transmissible to cattle and small ruminants. Our current knowledge of bovine atypical prion strains in sheep and goat relies only on experimental transmission studies by intracranial inoculation. To assess oral susceptibility of goats to L-BSE, we orally inoculated five goats with cattle L-BSE brain homogenates and investigated pathogenic prion protein (PrPsc) distribution by an ultrasensitive in vitro conversion assay known as Real-Time Quaking Induced Conversion (RT-QuIC). RESULTS: Despite a prolonged observation period of 80 months, all these animals and the uninfected controls did not develop clinical signs referable to TSEs and tested negative by standard diagnostics. Otherwise, RT-QuIC analysis showed seeding activity in five out of five examined brain samples. PrPsc accumulation was also detected in spinal cord and lymphoreticular system. These results indicate that caprine species are susceptible to L-BSE by oral transmission and that ultrasensitive prion tests deserve consideration to improve the potential of current surveillance systems against otherwise undetectable forms of animal prion infections.

Influence of Interspecies Transmission of Atypical Bovine Spongiform Encephalopathy Prions to Hamsters on Prion Characteristics.

Bovine spongiform encephalopathy (BSE) is a prion disease in cattle and is classified into the classical type (C-BSE) and two atypical BSEs, designated as high type (H-BSE) and low type (L-BSE). These classifications are based on the electrophoretic migration of the proteinase K-resistant core (PrPres) of the disease-associated form of the prion protein (PrPd). In a previous study, we succeeded in transmitting the H-BSE prion from cattle to TgHaNSE mice overexpressing normal hamster cellular PrP (PrPC). Further, Western blot analysis demonstrated that PrPres banding patterns of the H-BSE prion were indistinguishable from those of the C-BSE prion in TgHaNSE mice. In addition, similar PrPres glycoprofiles were detected among H-, C-, and L-BSE prions in TgHaNSE mice. Therefore, to better understand atypical BSE prions after interspecies transmission, H-BSE prion transmission from TgHaNSE mice to hamsters was investigated, and the characteristics of classical and atypical BSE prions among hamsters, wild-type mice, and mice overexpressing bovine PrPC (TgBoPrP) were compared in this study using biochemical and neuropathological methods. Identical PrPres banding patterns were confirmed between TgHaNSE mice and hamsters in the case of all three BSE prion strains. However, these PrPres banding patterns differed from those of TgBoPrP and wild-type mice infected with the H-BSE prion. In addition, glycoprofiles of TgHaNSE mice and hamsters infected with the L-BSE prion differed from those of TgBoPrP mice infected with the L-BSE prion. These data indicate that the PrPC amino acid sequences of new host species rather than other host environmental factors may affect some molecular aspects of atypical BSE prions. Although three BSE prion strains were distinguishable based on the neuropathological features in hamsters, interspecies transmission modified some molecular properties of atypical BSE prions, and these properties were indistinguishable from those of C-BSE prions in hamsters. Taken together, PrPres banding patterns and glycoprofiles are considered to be key factors for BSE strain typing. However, this study also revealed that interspecies transmission could sometimes influence these characteristics.

Estimation of prion infectivity in tissues of cattle infected with atypical BSE by real time-quaking induced conversion assay.

Atypical bovine spongiform encephalopathy (BSE), first identified in 2004, poses a threat due to the potential to spread the disease to cattle and other animals, including humans. Here, we estimated prion titers in various tissues of cattle infected with atypical BSE using a real-time quaking-induced conversion assay that detects amyloid seeding activity of a disease-specific prion protein, PrPSc, a major component of prions. PrPSc was detected both in and outside of nerve tissues, and some of the peripheral nerve tissues contained relatively high prion titers. Low titers of prions were also observed in masseter, jejunum, and adrenal glands. Quantitative data on prion infectivity in tissues of atypical BSE-affected cattle is useful to assess the risk of atypical BSE.

Intra- and Interspecies Transmission of Atypical BSE - What Can We Learn from It?

After the detection of the first cases of atypical bovine spongiform encephalopathy (BSE) more than ten years ago, the etiology, pathogenesis and agent distribution of these novel BSE forms in cattle were completely unknown. Many studies have been performed in the meantime to elucidate the pathogenic mechanisms of these diseases. A wealth of data has been accumulated regarding the distribution of the abnormal isoform of the prion protein, PrPSc, in tissues of affected cattle, confirming the general restriction of the PrPSc and agent distribution to the central and peripheral nervous system, albeit at slightly higher levels as compared to classical BSE. However, due to lack of data, the assumptions regarding the spontaneous etiology of both atypical BSE forms (H-BSE and L-BSE) and also the origin of the classical BSE epidemic are still mainly speculative. By performing subpassage experiments of both the atypical BSE forms in a variety of conventional and transgenic mice and Syrian Gold hamsters, we aimed to improve our understanding of the strain stability of these BSE forms. It turned out that under these experimental conditions, both the atypical BSE forms may alter their phenotypes and become indistinguishable from classical BSE. Information about the classical and atypical BSE strain characteristics help to improve our understanding of the correlation between all three BSE forms.

Encefalopatia espongiforme bovina atípica: uma revisão / Atypical bovine spongiform encephalopathy: a review

Bovine spongiform encephalopathy (BSE), caused by an infectious prion, emerged in the 1980s in Europe as a new disease in cattle and, since then, several actions are being taken for its prevention and control. Restricting the feeding of ruminants with animal by-products and the removal and destruction of specific risk materials (SRM) for the condition of carcasses in slaughterhouses have been proven effective to control the disease, in addition to the reduction of human exposure to the agent, as this is an important zoonosis. However, in 2004 the first atypical cases of BSE were diagnosed, in which the causative agents showed different molecular weights in Western blot (WB), compared to the classical form of the agent. In addition to the molecular differences, clinical presentations proved to be differentiated in atypical forms, affecting mainly cattle older than eight years. Because it is a new form of the disease, many studies are being conducted to elucidate the pathogenesis, epidemiology and zoonotic potential of atypical BSE. The aim of this study was to review the main aspects of atypical BSE emphasizing its etiology, epidemiology, clinical signs, diagnosis and control and prevention measures.

A encefalopatia espongiforme bovina (EEB), causada por um príon infectante, surgiu na década de 1980 na Europa como uma nova doença nos rebanhos bovinos e, desde então, estão sendo tomadas várias ações para sua prevenção e controle. A restrição da alimentação de ruminantes com subprodutos de origem animal e a remoção e destruição dos materiais de risco específico para a doença das carcaças em frigoríficos se mostraram efetivas medidas para o controle da doença, além de reduzirem a exposição humana ao agente, pois se trata de uma importante zoonose. No entanto, em 2004 os primeiros casos atípicos de EEB foram diagnosticados, nos quais os agentes causais apresentavam alterações de peso molecular na prova de Western blot, em relação ao agente da forma clássica. Além das diferenças moleculares dos agentes, as apresentações clínicas mostraram-se diferenciadas nas formas atípicas, acometendo principalmente bovinos com idade superior a oito anos. Por se tratar de uma nova forma da doença, muitos estudos estão sendo conduzidos buscando elucidar a patogenia, epidemiologia e seu potencial zoonótico. Objetivou-se neste estudo revisar os principais aspectos relacionados às EEB atípicas enfatizando sua etiologia, epidemiologia, sinais clínicos, diagnóstico e medidas de controle.

Encefalopatia espongiforme bovina atípica: uma revisão / Atypical bovine spongiform encephalopathy: a review

A encefalopatia espongiforme bovina (EEB), causada por um príon infectante, surgiu na década de 1980 na Europa como uma nova doença nos rebanhos bovinos e, desde então, estão sendo tomadas várias ações para sua prevenção e controle. A restrição da alimentação de ruminantes com subprodutos de origem animal e a remoção e destruição dos materiais de risco específico para a doença das carcaças em frigoríficos se mostraram efetivas medidas para o controle da doença, além de reduzirem a exposição humana ao agente, pois se trata de uma importante zoonose. No entanto, em 2004 os primeiros casos atípicos de EEB foram diagnosticados, nos quais os agentes causais apresentavam alterações de peso molecular na prova de Western blot, em relação ao agente da forma clássica. Além das diferenças moleculares dos agentes, as apresentações clínicas mostraram-se diferenciadas nas formas atípicas, acometendo principalmente bovinos com idade superior a oito anos. Por se tratar de uma nova forma da doença, muitos estudos estão sendo conduzidos buscando elucidar a patogenia, epidemiologia e seu potencial zoonótico. Objetivou-se neste estudo revisar os principais aspectos relacionados às EEB atípicas enfatizando sua etiologia, epidemiologia, sinais clínicos, diagnóstico e medidas de controle.(AU)

Bovine spongiform encephalopathy (BSE), caused by an infectious prion, emerged in the 1980s in Europe as a new disease in cattle and, since then, several actions are being taken for its prevention and control. Restricting the feeding of ruminants with animal by-products and the removal and destruction of specific risk materials (SRM) for the condition of carcasses in slaughterhouses have been proven effective to control the disease, in addition to the reduction of human exposure to the agent, as this is an important zoonosis. However, in 2004 the first atypical cases of BSE were diagnosed, in which the causative agents showed different molecular weights in Western blot (WB), compared to the classical form of the agent. In addition to the molecular differences, clinical presentations proved to be differentiated in atypical forms, affecting mainly cattle older than eight years. Because it is a new form of the disease, many studies are being conducted to elucidate the pathogenesis, epidemiology and zoonotic potential of atypical BSE. The aim of this study was to review the main aspects of atypical BSE emphasizing its etiology, epidemiology, clinical signs, diagnosis and control and prevention measures.(AU)