Atypical/Nor98 scrapie was first identified in 1998 in Norway. It is now considered as a worldwide disease of small ruminants and currently represents a significant part of the detected transmissible spongiform encephalopathies (TSE) cases in Europe. Atypical/Nor98 scrapie cases were reported in ARR/ARR sheep, which are highly resistant to BSE and other small ruminants TSE agents. The biology and pathogenesis of the Atypical/Nor98 scrapie agent in its natural host is still poorly understood. However, based on the absence of detectable abnormal PrP in peripheral tissues of affected individuals, human and animal exposure risk to this specific TSE agent has been considered low. In this study we demonstrate that infectivity can accumulate, even if no abnormal PrP is detectable, in lymphoid tissues, nerves, and muscles from natural and/or experimental Atypical/Nor98 scrapie cases. Evidence is provided that, in comparison to other TSE agents, samples containing Atypical/Nor98 scrapie infectivity could remain PrPSc negative. This feature will impact detection of Atypical/Nor98 scrapie cases in the field, and highlights the need to review current evaluations of the disease prevalence and potential transmissibility. Finally, an estimate is made of the infectivity loads accumulating in peripheral tissues in both Atypical/Nor98 and classical scrapie cases that currently enter the food chain. The results obtained indicate that dietary exposure risk to small ruminants TSE agents may be higher than commonly believed.
Experimental transmission of bovine spongiform encephalopathy to sheep has prompted the implementation of a surveillance plan of scrapie in small ruminants by the European Union in all member states. Since its start over 30 000 animals have been tested, and the first seven cases of sheep with detectable PrP res deposition in the central nervous system have been identified in Portugal. Notably, the pattern of PrP res distribution in the brainstem was different from that previously described for scrapie and consistent in all seven animals. Moreover, the profile of the electrophoretic mobility of PrP res after proteinase K treatment was equivalent in all cases analysed but distinct from that observed for scrapie. Notably, four animals had genotypes rarely associated with scrapie, including one animal homozygous for A 136 R 154 R 171. There were no cases found to exhibit vacuolation, a pattern of PrP res distribution or PrP res electrophoretic mobility corresponding to scrapie. These data reveal a putative atypical scrapie strain in Portugal not linked to specific Prnp genotypes. Scrapie affects sheep and goats and is the most common natural form of a group of diseases designated transmissible spongiform encephalopathies, which include Creutzfeldt-Jakob disease (CJD) of humans and bovine spongiform encephalopathy (BSE). Scrapie is endemic in several European Union (EU) countries and has been recognized, as a disease identity, for over 250 years (McGowan, 1922). To date, there are no apparent clinical or epidemiological data linking scrapie to human disease. However, since it has been shown that sheep could be experimentally infected with BSE (Foster et al., 1993), the possibility has been raised that BSE could have been accidentally introduced in this species. This would constitute a grave problem in terms of public health, since, in contrast to scrapie, BSE has been directly linked with a new form of CJD (Bruce et al., 1997; Collinge et al., 1996). Furthermore, it has been proposed that like scrapie, BSE in sheep could be naturally transmitted and thus become endemic (Foster et al., 2001). Clinically both diseases are indistinguishable (Foster et al., 2001). These possibilities prompted the EU to implement a surveillance scheme for scrapie in small ruminants.
Atypical/Nor98 scrapie (AS) is a prion disease of small ruminants. Currently there are no efficient measures to control this form of prion disease, and, importantly, the zoonotic potential and the risk that AS might represent for other farmed animal species remains largely unknown. In this study, we investigated the capacity of AS to propagate in bovine PrP transgenic mice. Unexpectedly, the transmission of AS isolates originating from 5 different European countries to bovine PrP mice resulted in the propagation of the classical BSE (c-BSE) agent. Detection of prion seeding activity in vitro by protein misfolding cyclic amplification (PMCA) demonstrated that low levels of the c-BSE agent were present in the original AS isolates. C-BSE prion seeding activity was also detected in brain tissue of ovine PrP mice inoculated with limiting dilutions (endpoint titration) of ovine AS isolates. These results are consistent with the emergence and replication of c-BSE prions during the in vivo propagation of AS isolates in the natural host. These data also indicate that c-BSE prions, a known zonotic agent in humans, can emerge as a dominant prion strain during passage of AS between different species. These findings provide an unprecedented insight into the evolution of mammalian prion strain properties triggered by intra- and interspecies passage. From a public health perspective, the presence of c-BSE in AS isolates suggest that cattle exposure to small ruminant tissues and products could lead to new occurrences of c-BSE.
BackgroundDuring the last decade, active surveillance for transmissible spongiform encephalopathies in small ruminants has been intensive in Europe. In many countries this has led to the detection of cases of atypical scrapie which, unlike classical scrapie, might not be contagious. EU legislation requires, that following detection of a scrapie case, control measures including further testing take place in affected flocks, including the culling of genotype susceptible to classical scrapie. This might result in the detection of additional cases. The aim of this study was to investigate the occurrence of additional cases in flocks affected by atypical scrapie using surveillance data collected in Europe in order to ascertain whether atypical scrapie, is contagious.ResultsQuestionnaires were used to collect, at national level, the results of active surveillance and testing associated with flock outbreaks in 12 European countries. The mean prevalence of atypical scrapie was 5.5 (5.0-6.0) cases per ten thousand in abattoir surveillance and 8.1 (7.3-9.0) cases per ten thousand in fallen stock. By using meta-analysis, on 11 out of the 12 countries, we found that the probability of detecting additional cases of atypical scrapie in positive flocks was similar to the probability observed in animals slaughtered for human consumption (odds ratio, OR = 1.07, CI95%: 0.70-1.63) or among fallen stock (OR = 0.78, CI95%: 0.51-1.2). In contrast, when comparing the two scrapie types, the probability of detecting additional cases in classical scrapie positive flocks was significantly higher than the probability of detecting additional cases in atypical scrapie positive flocks (OR = 32.4, CI95%: 20.7-50.7).ConclusionsThese results suggest that atypical scrapie is not contagious or has a very low transmissibility under natural conditions compared with classical scrapie. Furthermore this study stressed the importance of standardised data collection to make good use of the analyses undertaken by European countries in their efforts to control atypical and classical scrapie.
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