Classical Bovine Spongiform Encephalopathy Research Articles

Is there a decline in bovine spongiform encephalopathy cases born after reinforced feed bans? A modelling study in EU member states.

Occasional cases of classical bovine spongiform encephalopathy (BSE) still continue to occur within the European Union (EU) for animals born after reinforced feed bans (BARBs), which should in theory have eliminated all risk of infection. The study aimed to determine (i) whether a common rate of decline of BSE infection was evident across EU member states, i.e. to determine whether control measures have been equally effective in all member states, (ii) whether there was any evidence of spontaneous occurrence of BSE in the data and (iii) the expected date for the last BSE case in UK. It was found that there was no significant difference in the rate of decline of BSE prevalence between member states, with a common rate of decline of 33·9% per annum (95% CI 30·9-37%) in successive annual birth cohorts. Trend analysis indicated an ultimate decline to 0 prevalence, suggesting that spontaneous occurrence does not explain the majority of cases. Projecting forward the trends from the back-calculation model indicated that there was approximately a 50% probability of further cases in the UK, and should the current rate of decline continue, there remains the possibility of further occasional cases up until 2026.

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Lack of germline mutation at codon 211 of the prion protein gene (PRNP) in Korean native cattle - Short communication.

Bovine prion diseases are composed of two types of bovine spongiform encephalopathy (BSE), classical BSE and atypical BSE. Recent studies have identified one case of atypical BSE with an E211K mutation. E211K is homologous to the human E200K mutation, which is related to familial Creutzfeldt-Jakob disease (CJD), one of the familial forms of human prion diseases. To date, familial forms of prion diseases have not been reported in non-human animals. Because the familial forms of human prion diseases account for more than 10% of all human prion disease cases, the detection of the E211K mutation in healthy cattle is very important for verifying the role of this mutation as a familial form of BSE. To detect putative mutations related to familial BSE, specifically E211K in Korean native cattle (Hanwoo) and Korean dairy cattle (Holstein), we performed direct sequencing targeting codon 211 and the adjacent regions of the bovine prion protein (PRNP) gene in 384 Hanwoo and 152 Holstein cattle. We did not find the E211K mutation in any of the Korean cattle. Although we did not find the E211K mutation in Korean native cattle, E211K is a postulated mutation; therefore, further screening in other countries and larger samples is highly desirable.

Detection and partial discrimination of atypical and classical bovine spongiform encephalopathies in cattle and primates using real-time quaking-induced conversion assay.

The transmission of classical bovine spongiform encephalopathy (C-BSE) through contaminated meat product consumption is responsible for variant Creutzfeldt-Jakob disease (vCJD) in humans. More recent and atypical forms of BSE (L-BSE and H-BSE) have been identified in cattle since the C-BSE epidemic. Their low incidence and advanced age of onset are compatible with a sporadic origin, as are most cases of Creutzfeldt-Jakob disease (CJD) in humans. Transmissions studies in primates and transgenic mice expressing a human prion protein (PrP) indicated that atypical forms of BSE may be associated with a higher zoonotic potential than classical BSE, and require particular attention for public health. Recently, methods designed to amplify misfolded forms of PrP have emerged as promising tools to detect prion strains and to study their diversity. Here, we validated real-time quaking-induced conversion assay for the discrimination of atypical and classical BSE strains using a large series of bovine samples encompassing all the atypical BSE cases detected by the French Centre of Reference during 10 years of exhaustive active surveillance. We obtained a 100% sensitivity and specificity for atypical BSE detection. In addition, the assay was able to discriminate atypical and classical BSE in non-human primates, and also sporadic CJD and vCJD in humans. The RT-QuIC assay appears as a practical means for a reliable detection of atypical BSE strains in a homologous or heterologous PrP context.

Use of bovine recombinant prion protein and real-time quaking-induced conversion to detect cattle transmissible mink encephalopathy prions and discriminate classical and atypical L- and H-Type bovine spongiform encephalopathy.

Prions are amyloid-forming proteins that cause transmissible spongiform encephalopathies through a process involving conversion from the normal cellular prion protein to the pathogenic misfolded conformation (PrPSc). This conversion has been used for in vitro assays including serial protein misfolding amplification and real-time quaking induced conversion (RT-QuIC). RT-QuIC can be used for the detection of prions in a variety of biological tissues from humans and animals. Extensive work has been done to demonstrate that RT-QuIC is a rapid, specific, and highly sensitive prion detection assay. RT-QuIC uses recombinant prion protein to detect minute amounts of PrPSc. RT-QuIC has been successfully used to detect PrPSc from different prion diseases with a variety of substrates including hamster, human, sheep, bank vole, bovine and chimeric forms of prion protein. However, recombinant bovine prion protein has not been used to detect transmissible mink encephalopathy (TME) or to differentiate types of bovine spongiform encephalopathy (BSE) in samples from cattle. We evaluated whether PrPSc from TME and BSE infected cattle can be detected with RT-QuIC using recombinant bovine prion proteins, and optimized the reaction conditions to specifically detect cattle TME and to discriminate between classical and atypical BSE by conversion efficiency. We also found that substrate composed of the disease associated E211K mutant protein can be effective for the detection of TME in cattle and that wild type prion protein appears to be a practical substrate to discriminate between the different types of BSEs.

Assessing the time taken for a surveillance system to detect a re-emergence of bovine spongiform encephalopathy in cattle

During the bovine spongiform encephalopathy (BSE) epidemic in July 2001 the European Commission established a surveillance scheme for the comprehensive sampling of all BSE clinical suspects, healthy slaughter (HS) animals >30months, and all emergency slaughter and fallen stock animals tested when >24months. With the exponential decline in classical BSE cases, this comprehensive surveillance system has been successively modified to become risk-based, targeting those exit streams and ages where cases from the original epidemic are most likely to be detected. Such reductions in testing are not without losses in the information subsequently collected, which could affect the sensitivity of the surveillance system to relatively small changes in the underlying prevalence of BSE across the European Union (EU). Here we report on a cohort-based approach to estimate the time taken for EU surveillance to observe a theoretical re-emergence of BSE in cattle. A number of surveillance schemes were compared. The baseline scheme considered detection being triggered by at least one case in the ‘age window’ 48–72 months in the fallen stock or emergency slaughter exit streams. Alternative schemes changed the start and end of this age window as well as considering testing for HS cattle. Under the baseline scheme, an estimated 15 years would lapse ([2.5th, 97.5th] percentiles=[10,24]) prior to detection, during which time 2867 infected animals ([2.5th, 97.5th]=[1722,6967]) would enter the slaughter population. These animals would be predominantly young animals (majority <24months) showing no clinical signs. This baseline scheme reduced the time to detection by 2 years, compared to a scheme where only clinical suspects were tested assuming BSE symptoms are recognised to the same degree by veterinary surgeons. Additional testing of younger animals did not improve detection as young infected animals were unlikely to test positive, but testing of older animals reduced the time to detection. Testing of HS animals >72months reduced the time to detection by one year compared to the baseline model, but would incur a high financial cost, e.g. testing HS animals >72months of age for 14 years would entail approximately 50.4 million additional tests. A limitation of the results is that there is no guarantee that current detection methods, optimised for detection of classical BSE, would identify a novel prion disease in cattle and it is currently difficult to envisage plausible routes by which a re-emergence of classical BSE could occur in Europe.

PrP-C1 fragment in cattle brains reveals features of the transmissible spongiform encephalopathy associated PrPsc

Three different types of bovine spongiform encephalopathy (BSE) are known and supposedly caused by distinct prion strains: the classical (C-) BSE type that was typically found during the BSE epidemic, and two relatively rare atypical BSE types, termed H-BSE and L-BSE. The three BSE types differ in the molecular phenotype of the disease associated prion protein, namely the N-terminally truncated proteinase K (PK) resistant prion protein fragment (PrPres). In this study, we report and analyze yet another PrPres type (PrPres-2011), which was found in severely autolytic brain samples of two cows in the framework of disease surveillance in Switzerland in 2011. Analysis of brain tissues from these animals by PK titration and PK inhibitor assays ruled out the process of autolysis as the cause for the aberrant PrPres profile. Immunochemical characterization of the PrP fragments present in the 2011 cases by epitope mapping indicated that PrPres-2011 corresponds in its primary sequence to the physiologically occurring PrP-C1 fragment. However, high speed centrifugation, sucrose gradient assay and NaPTA precipitation revealed biochemical similarities between PrPres-2011 and the disease-associated prion protein found in BSE affected cattle in terms of detergent insolubility, PK resistance and PrP aggregation. Although it remains to be established whether PrPres-2011 is associated with a transmissible disease, our results point out the need of further research on the role the PrP-C1 aggregation and misfolding in health and disease.

In vitro amplification of H-type atypical bovine spongiform encephalopathy by protein misfolding cyclic amplification

ABSTRACTThe in vitro amplification of prions by serial protein misfolding cyclic amplification has been shown to detect PrPSc to levels at least as sensitive as rodent bioassay but in a fraction of the time. Bovine spongiform encephalopathy is a zoonotic prion disease in cattle and has been shown to occur in 3 distinct forms, classical BSE (C-BSE) and 2 atypical BSE forms (L-BSE and H-BSE). Atypical forms are usually detected in asymptomatic, older cattle and are suggested to be spontaneous forms of the disease. Here, we show the development of a serial protein misfolding cyclic amplification method for the detection of H-BSE. The assay could detect PrPSc from 3 distinct experimental isolates of H-BSE, could detect PrPSc in as little as 1×10−12 g of brain material and was highly specific. Additionally, the product of serial protein misfolding cyclic amplification at all dilutions of seed analyzed could be readily distinguished from L-BSE, which did not amplify, and C-BSE, which had PrPSc with distinct protease K-resistance and protease K-resistant PrPSc molecular weights.

Atypical BSE: Current Knowledge and Knowledge Gaps.

Atypical BSE is an invariably fatal neurologic disease of cattle caused by misfolded prion proteins with different conformations than those associated with classical BSE. Evidence suggests that these atypical BSE types are sporadic or genetic prion diseases of cattle and the relevance of these diseases, as far as natural transmissibility, is still unknown. Different misfolded prion protein conformations also result in unique biochemical characteristics. This raised concerns about detection of atypical BSE on rapid test platforms designed and validated for classical BSE prions. Despite the differences in the misfolded prion protein characteristics, studies have shown that the tests also work well for detecting the known types of atypical BSE. A new question that has recently emerged is related to the possibility of additional forms of atypical BSE. Initially reactive bovine brain samples on certain rapid surveillance tests have sparked debate about the true BSE status of these samples. Work is currently underway to determine if these samples are infectious and if they eventually result in neurologic disease in cattle. Results of these studies could impact future BSE diagnostic testing programs as well as human and animal health policies.

Phenotypical Variability in Bovine Spongiform Encephalopathy: Epidemiology, Pathogenesis, and Diagnosis of Classical and Atypical Forms.

After thirty years, bovine spongiform encephalopathy (BSE) still represents the biggest crisis in the field of food safety. Initially detected in the United Kingdom in 1986, BSE spread to many other countries all over the world, involving approximately 200,000 cattle. The origin of BSE is uncertain, but epidemiological studies suggest that the source was cattle feed prepared from prion-infected animal tissues. The implementation of the drastic measures, including the ban of meat and bone meal from livestock feed and the removal of specified risk material from the food chain, has eventually resulted in a significant decline of the epidemic. For many years, it was believed that the disease was caused by transmission of a single prion strain. However, since 2004 two types of BSE, with distinct phenotypical characteristics, have been detected in Italy and France. These atypical types are characterized by distinct Western Blot profiles of abnormal protease-resistant prion protein, named high-type (H-BSE) and low-type (L-BSE). At present, there is no comprehensive information about the origin of the atypical BSEs (sporadic vs. acquired), and data about the pathogenesis of both atypical forms are very limited as compared to the classical type (C-BSE). This chapter will provide a well-organized overview of what is known about classical and atypical BSE. It will review information on the main epidemiological features, pathogenesis, and the criteria for routine diagnosis based on rapid tests, histological, immunohistochemical, and Western blot analysis. Furthermore, a brief overview about the most recently in vitro techniques will be also provided.

Prions and animal transmissible spongiform encephalopathies

Background. Transmissible spongiform encephalopathies (TSEs) or prion diseases are a unique group of neurodegenerative diseases of animals and humans, which always have a fatal outcome and are transmissible among animals of the same or different species. Scope and Approach. The aim of this work is to review some recent data about animal TSEs, with the emphasis on their causative agents and zoonotic potential, and to discuss why the surveillance and control measures over animal TSEs should remain in force. Key Findings and Conclusions. We still have incomplete knowledge of prions and prion diseases. Scrapie has been present for a very long time and controlled with varied success. Bovine spongiform encephalopathy (BSE) emerged unnoticed, and spread within a few years to epidemic proportions, entailing enormous economic consequences and public concerns. Currently, the classical BSE epidemic is under control, but atypical cases do, and probably will, persist in bovine populations. The Chronic Wasting Disease (CWD) of the cervids has been spreading in North America and has recently been detected in Europe. Preventive measures for the control of classical BSE remain in force, including the feed ban and removal of specified risk materials. However, active BSE surveillance has considerably decreased. In the absence of such preventive and control measures, atypical BSE cases in healthy slaughtered bovines might persist in the human food chain, and BSE prions might resurface. Moreover, other prion strains might emerge and spread undetected if the appropriate preventive and surveillance measures were to cease, leaving behind inestimable consequences.

The European Union summary report on data of the surveillance of ruminants for the presence of transmissible spongiform encephalopathies (TSEs) in 2015

This report of EFSA presents the results of surveillance activities on transmissible spongiform encephalopathies (TSEs) in bovine animals, sheep and goats as well as genotyping data in sheep, carried out in 2015 in the EU and in three non-Member States (non-MS). Since 2001, approximately 114 million cattle in the EU have been tested for bovine spongiform encephalopathy (BSE) according Regulation (EC) 999/2001. In 2015, 1.4 million bovine animals were tested and five cases were detected in four MS (Ireland: one case; Slovenia: one case; Spain: one case; and the United Kingdom: two cases) and one case was detected in Norway. Two cases (in Ireland and the United Kingdom) were affected by classical BSE and both cases were born after the EU-wide feed ban enforced in 2001. The remaining four cases were atypical BSE cases (three H-BSE type and one L-BSE type). Since 2002, approximately 8.4 million small ruminants have been tested during the EU-wide surveillance for scrapie. In 2015, 319,638 sheep and 135,857 goats were tested. In total, 641 scrapie cases in sheep were detected in 18 MS while 1,052 scrapie cases in goats were detected in nine MS, respectively. In two non-MS (Iceland and Norway), 40 scrapie cases in sheep were detected. Although in a number of MS the decrease in classical scrapie is clear, at the EU level there is no clear decreasing trend in the occurrence of scrapie in small ruminants. Results obtained from genotyping in sheep confirm that cases of classical scrapie are clustered among certain genotypes, and animals with these genotypes seem to account for less than 20% of the European randomly sampled sheep population. In total, 580 samples from species other than domestic ruminants were tested for TSE in three MS, all with negative results.

Absence of Evidence for a Causal Link between Bovine Spongiform Encephalopathy Strain Variant L-BSE and Known Forms of Sporadic Creutzfeldt-Jakob Disease in Human PrP Transgenic Mice.

Since the quasi-extinction of classical BSE, atypical BSE forms are the sole BSE variants circulating in cattle worldwide. They are observed in rare cases of old cattle, making them difficult to detect. Extrapolation of our results suggests that L-BSE may propagate in humans as an unrecognized form of CJD, and we urge both the continued utilization of precautionary measures to eliminate these agents from the human food chain and active surveillance for CJD phenotypes in the general population.

Goat K222-PrPC polymorphic variant does not provide resistance to atypical scrapie in transgenic mice.

Host prion (PrPC) genotype is a major determinant for the susceptibility to prion diseases. The Q/K222-PrPC polymorphic variant provides goats and mice with high resistance against classical scrapie and bovine spongiform encephalopathy (BSE); yet its effect against atypical scrapie is unknown. Here, transgenic mice expressing the goat wild-type (wt) or the K222-PrPC variant were intracerebrally inoculated with several natural cases of atypical scrapie from sheep and goat and their susceptibility to the prion disease was determined. Goat wt and K222-PrPC transgenic mice were 100% susceptible to all the atypical scrapie isolates, showing similar survival times and almost identical disease phenotypes. The capacity of the K222-PrPC variant to replicate specifically the atypical scrapie strain as efficiently as the goat wt PrPC, but not the classical scrapie or cattle-BSE as previously reported, further suggests the involvement of concrete areas of the host PrPC in the strain-dependent replication of prions.

A Comparison of Classical and H-Type Bovine Spongiform Encephalopathy Associated with E211K Prion Protein Polymorphism in Wild-Type and EK211 Cattle Following Intracranial Inoculation.

In 2006, a case of H-type bovine spongiform encephalopathy (BSE-H) was diagnosed in a cow that was associated with a heritable polymorphism in the bovine prion protein gene (PRNP) resulting in a lysine for glutamate amino acid substitution at codon 211 (called E211K) of the prion protein. Although the prevalence of this polymorphism is low, cattle carrying the K211 allele may be predisposed to rapid onset of BSE-H when exposed or to the potential development of a genetic BSE. This study was conducted to better understand the relationship between the K211 polymorphism and its effect on BSE phenotype. BSE-H from the US 2006 case was inoculated intracranially (IC) in one PRNP wild-type (EE211) calf and one EK211 calf. In addition, one wild-type calf and one EK211 calf were inoculated IC with brain homogenate from a US 2003 classical BSE case. All cattle developed clinical disease. The survival time of the E211K BSE-H inoculated EK211 calf (10 months) was shorter than the wild-type calf (18 months). This genotype effect was not observed in classical BSE inoculated cattle (both 26 months). Significant changes in retinal function were observed in H-type BSE challenged cattle only. Cattle challenged with the same inoculum showed similar severity and neuroanatomical distribution of vacuolation and disease-associated prion protein deposition in the brain, though differences in neuropathology were observed between E211K BSE-H and classical BSE inoculated animals. Western blot results for brain tissue from challenged animals were consistent with the inoculum strains. This study demonstrates that the phenotype of E211K BSE-H remains stable when transmitted to cattle without the K211 polymorphism, and exhibits a number of features that differ from classical BSE in both wild-type and heterozygous EK211 animals.

Abnormalities in Brainstem Auditory Evoked Potentials in Sheep with Transmissible Spongiform Encephalopathies and Lack of a Clear Pathological Relationship.

Scrapie is transmissible spongiform encephalopathy (TSE), which causes neurological signs in sheep, but confirmatory diagnosis is usually made postmortem on examination of the brain for TSE-associated markers like vacuolar changes and disease-associated prion protein (PrPSc). The objective of this study was to evaluate whether testing of brainstem auditory evoked potentials (BAEPs) at two different sound levels could aid in the clinical diagnosis of TSEs in sheep naturally or experimentally infected with different TSE strains [classical and atypical scrapie and bovine spongiform encephalopathy (BSE)] and whether any BAEP abnormalities were associated with TSE-associated markers in the auditory pathways. BAEPs were recorded from 141 clinically healthy sheep of different breeds and ages that tested negative for TSEs on postmortem tests to establish a reference range and to allow comparison with 30 sheep clinically affected or exposed to classical scrapie (CS) without disease confirmation (test group 1) and 182 clinically affected sheep with disease confirmation (test group 2). Abnormal BAEPs were found in 7 sheep (23%) of group 1 and 42 sheep (23%) of group 2. The proportion of sheep with abnormalities did not appear to be influenced by TSE strain or PrPSc gene polymorphisms. When the magnitude of TSE-associated markers in the auditory pathways was compared between a subset of 12 sheep with and 12 sheep without BAEP abnormalities in group 2, no significant differences in the total PrPSc or vacuolation scores in the auditory pathways could be found. However, the data suggested that there was a difference in the PrPSc scores depending on the TSE strain because PrPSc scores were significantly higher in sheep with BAEP abnormalities infected with classical and L-type BSE, but not with CS. The results indicated that BAEPs may be abnormal in sheep infected with TSEs but the test is not specific for TSEs and that neither vacuolation nor PrPSc accumulation appears to be responsible for the clinical abnormalities.

Current understanding of PrnP Genetics: A tool for Molecular Assisted Selection in Sheep Populations (A review)

Scrapie is a neurodegenerative prion disease of sheep, goats and mouflons, belonging to the group of transmissible spongiform encephalopathies (TSEs), which affects humans as well. Even though classical scrapie has been known for over 250 years, the 1985 BSE crisis related to the advent of new forms of the Creutzfeldt-Jakob disease (vCJD) in humans imposed the implementation of rapid coercive legal measures of prevention, control and eradication of TSEs. According to the prion hypothesis, the transmissible agent is the pathological isoform (PrP Sc ) of cellular prion protein (PrP C ). Specific polymorphisms of the gene that encodes cell prion protein (PrnP) in sheep have been associated with resistance / natural susceptibility to the development and progression of the disease. Combinations of alleles at three adjacent codons (136 [A/V], 154 [H/R], 171 [H/Q/R]) underpin the classification of 15 possible genotypes in risk classes, applicable in selection schemes where the maximum resistance is conferred by ARR allele, and the minimum by the VRQ allele. Although, after applying these programmes, the genetic structure of sheep populations has changed favourably, genotype association studies showed that no genotype is completely resistant to the infection, including homozygote ARR / ARR. With the discovery of atypical scrapie (Nor98), it became evident that the connection between the genetics of prion protein gene polymorphisms and susceptibility to the disease must be re-evaluated individually for each breed. In scrapie monitoring and control programmes, three diagnostic categories of the disease are observed: classical scrapie, atypical scrapie and BSE scrapie in small ruminant. This review shows the chronology of progress in the fight for the eradication of TSEs in sheep, 30 years after the BSE epidemic outburst, focusing especially on the link between the molecular diagnostic forms and the genetics of the disease. Â

Whole Blood Gene Expression Profiling in Preclinical and Clinical Cattle Infected with Atypical Bovine Spongiform Encephalopathy.

Prion diseases, such as bovine spongiform encephalopathies (BSE), are transmissible neurodegenerative disorders affecting humans and a wide variety of mammals. Variant Creutzfeldt-Jakob disease (vCJD), a prion disease in humans, has been linked to exposure to BSE prions. This classical BSE (cBSE) is now rapidly disappearing as a result of appropriate measures to control animal feeding. Besides cBSE, two atypical forms (named H- and L-type BSE) have recently been described in Europe, Japan, and North America. Here we describe the first wide-spectrum microarray analysis in whole blood of atypical BSE-infected cattle. Transcriptome changes in infected animals were analyzed prior to and after the onset of clinical signs. The microarray analysis revealed gene expression changes in blood prior to the appearance of the clinical signs and during the progression of the disease. A set of 32 differentially expressed genes was found to be in common between clinical and preclinical stages and showed a very similar expression pattern in the two phases. A 22-gene signature showed an oscillating pattern of expression, being differentially expressed in the preclinical stage and then going back to control levels in the symptomatic phase. One gene, SEL1L3, was downregulated during the progression of the disease. Most of the studies performed up to date utilized various tissues, which are not suitable for a rapid analysis of infected animals and patients. Our findings suggest the intriguing possibility to take advantage of whole blood RNA transcriptional profiling for the preclinical identification of prion infection. Further, this study highlighted several pathways, such as immune response and metabolism that may play an important role in peripheral prion pathogenesis. Finally, the gene expression changes identified in the present study may be further investigated as a fingerprint for monitoring the progression of disease and for developing targeted therapeutic interventions.

Detection of Atypical H-Type Bovine Spongiform Encephalopathy and Discrimination of Bovine Prion Strains by Real-Time Quaking-Induced Conversion.

Prion diseases of cattle include the classical bovine spongiform encephalopathy (C-BSE) and the atypical H-type BSE (H-BSE) and L-type BSE (L-BSE) strains. Although the C- and L-BSE strains can be detected and discriminated by ultrasensitive real-time quaking-induced conversion (RT-QuIC) assays, no such test has yet been described for the detection of H-BSE or the discrimination of each of the major bovine prion strains. Here, we demonstrate an RT-QuIC assay for H-BSE that can detect as little as 10(-9) dilutions of brain tissue and neat cerebrospinal fluid samples from clinically affected cattle. Moreover, comparisons of the reactivities with different recombinant prion protein substrates and/or immunoblot band profiles of proteinase K-treated RT-QuIC reaction products indicated that H-, L-, and C-BSE have distinctive prion seeding activities and can be discriminated by RT-QuIC on this basis.

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.