Instruct: Given a question, retrieve relevant documents that can help answer the question.
Query: Why is Scrapie called such?
The name scrapie is derived from one of the clinical signs of the condition, wherein affected animals will compulsively scrape off their fleeces against rocks, trees, or fences. The disease apparently causes an itching sensation in the animals. Other clinical signs include excessive lip smacking, altered gaits, and convulsive collapse.[6]
In the 5th century BCE, Hippocrates described a disease like TSE in cattle and sheep, which he believed also occurred in man. Publius Flavius Vegetius Renatus records cases of a disease with similar characteristics in the 4th and 5th centuries AD. In 1755, an outbreak of scrapie was discussed in the British House of Commons and may have been present in Britain for some time before that. Although there were unsupported claims in 1759 that the disease was contagious, in general it was thought to be due to inbreeding and countermeasures appeared to be successful. Early-20th-century experiments failed to show transmission of scrapie between animals, until extraordinary measures were taken such as the intra-ocular injection of infected nervous tissue. No direct link between scrapie and disease in man was suspected then or has been found since. TSE was first described in man by Alfons Maria Jakob in the 1921. Daniel Carleton Gajdusek's discovery that Kuru was transmitted by cannibalism accompanied by the finding of scrapie-like lesions in the brains of Kuru victims strongly suggested an infectious basis to TSE. A paradigm shift to a non-nucleic infectious entity was required when the results were validated with an explanation of how a prion protein might transmit spongiform encephalopathy. Not until 1988 was the neuropathology of spongiform encephalopathy properly described in cows. The alarming amplification of BSE in the British cattle herd heightened fear of transmission to humans and reinforced the belief in the infectious nature of TSE. This was confirmed with the identification of a Kuru-like disease, called new variant Creutzfeldt–Jakob disease, in humans exposed to BSE. Although the infectious disease model of TSE has been questioned in favour of a prion transplantation model that explains why cannibalism favours transmission, the search for a viral agent is being continued in some laboratories.
For a detailed risk assessment of scrapie-contaminated soil, it was of major importance to analyze whether the detectable PrPSc in the soil extracts still exhibited oral infectivity after incubation times up to 29 months. A bioassay with Syrian hamsters was performed by feeding the animals with contaminated soil or aqueous soil extracts that had been collected after soil incubation for 26 and 29 months, respectively. Hamsters fed with contaminated soil exhibited their first scrapie-associated symptoms at two weeks to six months (95% CI) after the first feeding. The hamsters reached the terminal stage of scrapie at five to 21 months (95% CI) after the first feeding. This indicated substantial amounts of persistent infectivity in soil that had been incubated for 26 and 29 months.[30] In Iceland in 1978, a program was implemented to eradicate scrapie, and affected flocks were culled, premises were disinfected, and sheep houses were burnt; after two to three years, the premises were restocked with lambs from scrapie-free areas. Between 1978 and 2004, scrapie recurred on 33 farms. Nine recurrences occurred 14–21 years after culling as a result of persistent environmental contamination with PrPSc.[42]
Bastian challenges the widely popular theory that the TSEs are caused by prions, which are composed entirely of misfolded proteins. He claims instead that the TSEs are caused by an extremely small, cell wall deficient bacterium called "Spiroplasma", and that prions are the result of the disease process. The lack of a cell wall means it is not susceptible to most common antibiotics such as penicillin, which target cell wall synthesis. Bastian first found "Spiroplasma" in the brain of a CJD patient in an autopsy in 1979. He later demonstrated that "Spiroplasma mirum" strain SMCA (suckling mouse cataract agent) induces a microcystic spongiform encephalopathy in suckling rats that is similar to rat CJD. In 2007 he isolated "Spiroplasma" from scrapie and Chronic wasting disease (a TSE affecting deer, elk, and moose, abbreviated CWD), cultured them, and inoculated them into sheep and deer. According to Bastian, the scrapie and CWD "Spiroplasma" isolates caused a spongiform encephalopathy identical to scrapie and CWD.
In 1971, Dickinson, AG and Meikle, VM provided a hypothesis for the replication of the scrapie agent. This hypothesis was based on the discovery of a single autosomal gene controlling the scrapie incubation period in mice and on observations about strains of the scrapie agent. They dubbed the gene sinc for scrapie incubator. This hypothesis proposed that the gene products of each sinc allele contributed to a multimeric protein structure, which then formed a 'replication site' for the scrapie agent. The replication of the agent would depend on how the particular strain interacted with the replication site and of what the site was composed. The fact that different strains of scrapie were known had suggested the agent was similar to conventional viruses in that it carried a genome composed of nucleic acids. Thus, variants could arise during incubation, giving rise to new strains. No host-encoded properties were found to determine scrapie agent strain differences. This was thought to prove that the genome of the agent could vary independently and, although replicated by normal host mechanisms, was not coded by the host. The term 'virino' was coined to reflect the small size, immunological neutrality, and virus-like nature of the infectious particles.
Scrapie is infectious and transmissible among conspecifics, so one of the most common ways to contain it (since it is incurable) is to quarantine and destroy those affected. However, scrapie tends to persist in flocks and can also arise apparently spontaneously in flocks that have not previously had cases of the disease. The mechanism of transmission between animals and other aspects of the biology of the disease are only poorly understood, and these are active areas of research. Recent studies suggest prions may be spread through urine and persist in the environment for decades.[7]
Historically, scrapie had been considered to be an animal health issue. However, between 1996 and 1999 the UK SEAC had been considering the control and eradication of scrapie in the UK also with public health in mind because of concern over five issues:[14]
Scrapie is a fatal, degenerative disease that affects the nervous systems of sheep and goats.[1] It is one of several transmissible spongiform encephalopathies (TSEs), which also includes bovine spongiform encephalopathy (BSE or "mad cow disease"), Creutzfeldt-Jakob disease (CJD) in humans, and chronic wasting disease in deer. Like other spongiform encephalopathies, the cause of scrapie is unknown, but is thought to be caused by an infectious misfolded protein called a prion.[2][3] Scrapie has been known since 1732, and does not appear to be transmissible to humans.[4][5]
Scrapie usually affects sheep around three to five years of age. The potential for transmission at birth and from contact with placental tissues is apparent.
Several scientific observations remain unexplained by the prion hypothesis: It is known that mice with severe combined immunodeficiency do not develop scrapie following inoculation with brain tissue from animals infected with scrapie, suggesting that either the role of immunity in prion pathogenesis is incompletely understood or that there is some other flaw in current understanding of prion pathophysiology.[11] More recently, it has been shown that scrapie and Creutzfeldt–Jakob disease may require agent-specific nucleic acids for transmission of infection.[12] For these reasons, the prion/TSE hypothesis incompletely accounts for the observed data.[13]
In the UK, the Blair ministry implemented in 2001 a National Scrapie Plan, which encouraged breeding from sheep that are genetically more resistant to scrapie. This is intended to eventually reduce the incidence of the disease in the UK sheep population.[22][23] Scrapie occurs in Europe and North America, but to date, Australia and New Zealand (both major sheep-producing countries) are scrapie-free. In 2003, there was pressure from previously-sinistered Canadian husbandry practitioners on the Chretien government and their CFIA to implement their own NSP.[12]
Since 1998 and the mad cow epidemics, an EU directive forbids the production of "smalahove" from adult sheep, due to fear of the possibility of transmission of scrapie, a deadly, degenerative prion disease of sheep and goats, though scrapie does not appear to be transmissible to humans. It is now only allowed to be produced from the heads of lambs.
"With scrapie, the archetypical TSE, which is a natural disease in sheep and goats, the disease can appear suddenly in a flock in the absence of any known exposure to infected flocks (Palsson, 1979). Finally, fields in Iceland, that were left empty for up to 3 years after the destruction of scrapie-infected flocks, were repopulated with known scrapie-free sheep, and some of the sheep in this latter group subsequently developed scrapie (Palsson, 1979). This last 'experiment in nature' has yielded similar results a number of times in Iceland and in the United Kingdom. In one Icelandic farm, flocks have been eradicated three times; each time, the farm was left without sheep for 2 years, and after restocking with sheep from scrapie-free areas, the disease reappeared. Several years ago, a suggestion was made (S Sigurdarson, personal communication) that hay mites would be a good candidate as a vector for scrapie; this led to infection of mice with mite samples prepared from hay obtained from five Icelandic farms. Ten of these 71 mice became sick after injection with mite preparations from three of the five farms (Wisniewski et al, 1996; Rubenstein et al, 1998). The incubation periods ranged from 340 days to 626 days, and these mice had the protease-resistant form PrpSc, of a host-coded glycoprotein, PrPc . The protease-resistant form is a marker of TSE disease (Prusiner, 1991; Parchi et al, 1996). For some of these clinically positive mice, the banding pattern on WB analysis was unique (Wisniewski et al, 1996; Rubenstein et al, 1998)."[45]
In 2010, a team from New York described detection of PrPSc even when initially present at only one part in a hundred billion (10−11) in brain tissue. The method combines amplification with a novel technology called surround optical fiber immunoassay and some specific antibodies against PrPSc. The technique allowed detection of PrPSc after many fewer cycles of conversion than others have achieved, substantially reducing the possibility of artefacts, as well as speeding up the assay. The researchers also tested their method on blood samples from apparently healthy sheep that went on to develop scrapie. The animals' brains were analysed once any symptoms became apparent. They could therefore compare results from brain tissue and blood taken once the animals exhibited symptoms of the diseases, with blood obtained earlier in the animals' lives, and from uninfected animals. The results showed very clearly that PrPSc could be detected in the blood of animals long before the symptoms appeared. After further development and testing, this method could be of great value in surveillance as a blood- or urine-based screening test for scrapie.[27][28]
Thus, in the nucleotide model proposed by Dickinson, AG, and Outram, GW in 1979, the lifecycle of the scrapie agent included a stage where the genome was bound to host protein, probably a multimeric protein complex (now commonly known as a prion), derived from the "sinc" gene. Recalling Enrico Fermi's word play on a neutron-like particle, Outram coined the term 'virino' to describe a small virus. In the virino model, the host protein protects the scrapie agent nucleic acids from degradation and prevents the host from raising an immune response, since the protein/nucleic acid complex is seen as a legitimate part of the host. However, the presumed scrapie-associated nucleic acid has not been identified, and physical or chemical evidence for its presence is lacking.
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Post mortem examination is important for the diagnosis of scrapie. Histology of tissues shows accumulation of prions in the central nervous system, and immunohistochemical staining and ELISA can also be used to demonstrate the protein.
Kuru was shown to have remarkable similarity to scrapie, a disease of sheep and goats caused by an unconventional infectious agent. Subsequently, additional human agents belonging to the same group were discovered. They include sporadic, familial, and variant Creutzfeldt–Jakob disease. Gajdusek recognized that diseases like Kuru and Creutzfeldt–Jakob disease were caused by a new infectious agent that had not yet been identified. Further research on the scrapie agent by Stanley Prusiner and others led to the identification of endogenous proteins called prions as the cause of these diseases.
The cause of scrapie, as with other transmissible spongiform encephalopathies, is unknown and is a matter of debate;[15] the agent is very difficult to destroy with heat, radiation and disinfectants, does not evoke any detectible immune response, and has a long incubation period of between 18 months and 5 years.[16] The agent is thought to be much smaller than the smallest currently known virus and the prevailing theory is that it is caused by a misfolded protein called a prion. Prions multiply by causing normally folded proteins of the same type to take on their abnormal shape, which then go on to do the same, in a kind of chain reaction. These abnormal proteins are gradually accumulated in the body, especially in nerve cells, which subsequently die.
Several different types of PrPsc occur in the brains of animals with scrapie. As PrPs consist only of peptides, there is no known mechanism by which different prion types can occur. The mechanism by which the number of PrPsc molecules increases by orders-of-magnitude remains unexplained. There has been no satisfactory explanation as to how prion peptides with the same amino acid sequence change their 3-dimensional folding structure from an alpha helix to a beta sheet. The presence of damaged neurologic tissue is consistent with other hypotheses besides a prion. Inexplicably, mice with severe combined immunodeficiency do not develop scrapie following inoculation with brain tissue from animals infected with scrapie.
(includes photo of a sheep with scrapie) US Department of Agriculture of infected sheep demonstrating Hopping Gait – opinion article by Frank Bastian that proposes a different causation for scrapie and other prion diseases
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Contaminated Louping-ill vaccine. Also known as the 1935 Moredun Louping-ill Vaccine Disaster..[33] More than 1,500 sheep developed scrapie following vaccination. "An investigation into the etiology of scrapie followed the vaccination of sheep for louping-ill virus with formalin-treated extracts of ovine lymphoid tissue unknowingly contaminated with scrapie prions (Gordon 1946). Two years later, more than 1500 sheep developed scrapie from this vaccine." [34] "This vaccine was manufactured using formalised sheep brains contaminated with scrapie agent" [35] "At the 1946 National Veterinary Medical Association of Great Britain and Ireland Annual Congress, W. S. Gordon, PhD, presented evidence of scrapie transmission by way of a vaccine for louping-ill." "Dr. Gordon developed an effective vaccine to prevent louping-ill during 1931-32. After four years of field trials, his vaccine was produced in three batches for widespread use in 1935. The vaccine was made from brain, spinal cord, and spleen tissues taken from sheep five days after they had received an intracerebral inoculation of louping-ill virus. Formalin was added to the 10% saline suspension to inactivate the virus. During 1935 and 1936, no ill effects were noted in inoculated animals. Then two owners reported scrapie in their Blackface sheep who had been inoculated with louping-ill vaccine (batch 2) two and a half years earlier. Scrapie had not been seen in the Blackface breed before this. Upon investigation Dr. Gordon discovered that 8 lambs used to make batch 2 had been born to ewes who had been exposed to scrapie; some of the ewes developed scrapie in 1936-7. Dr. Gordon hypothesized that an "infective agent of scrapie" was present in the lambs' tissues used to make batch 2 and that this agent "could withstand a concentration of formalin...which inactivated the virus of louping ill; it could be transmitted by subcutaneous inoculation; it had an incubative period of two years or longer." A four-and-a-half-year experiment involving '788 sheep was initiated by the Animal Disease Research Association in 1938. The researchers found that 60% of normal sheep inoculated intracerebrally with saline suspensions of brain and spinal cord tissue taken from sheep with scrapie developed scrapie within those four-and-a-half-years. The incubation period was seven months and up. Only 30% of the sheep receiving a subcutaneous inoculation of the suspension developed scrapie in that time, and the incubation period in this group was 15 months and up. The researchers concluded that the infective agent was probably a filtrable virus." [36] Contaminated Mycoplasma agalactiae vaccine. In 1997 and 1998 there was an outbreak of scrapie in sheep and goats in Italy, and the cause was attributed to the vaccine. "An accidental infection from a vaccine was suggested as the explanation for the sudden increase in outbreaks of scrapie in Italy in 1997 and 1998. This paper describes a recent outbreak of scrapie in sheep and goats which were exposed to the same vaccine. No ewes or goats had been imported into the herd since 1992, but a vaccine against Mycoplasma agalactiae had been administered twice, in 1995 and 1997. High rates of crude mortality and scrapie incidence were experienced by both species, all birth cohorts were involved and a large proportion of aged animals was affected. A pattern of brain lesions was observed, with slight differences between the sheep and goats, which was very similar to the pattern observed in animals previously exposed to the same vaccine but clearly different from that observed in the brains of sheep with scrapie in a flock not exposed to the vaccine. Regardless of their exposure status, genotype analysis of the sheep showed the presence of polymorphism only at codon 171. The patterns of both incidence and brain lesions provide evidence that the epidemic of scrapie was due to the use of the vaccine." [37] "An accidental intra- and interspecies transmission of scrapie occurred in Italy in 1997 and 1998 following exposure to a vaccine against Mycoplasma agalactiae. PrP(Sc) in affected sheep and goats, collected from a single flock exposed to vaccination 2 years earlier, was molecularly typed. In five animals with iatrogenic scrapie, a PrP(Sc) type with a 20 kDa core fragment was found in all areas of the brain investigated. In three sheep and one goat, this isoform co-occurred with a fully glycosylated isoform that had a protease-resistant backbone of 17 kDa, whereas in two sheep and four goats, the two PrP(Sc) types were detected in different regions of the brain. In sheep with natural field scrapie, a PrP(Sc) type with physico-chemical properties indistinguishable from the 20 kDa isoform was found. The present results suggest the co-presence of two prion strains in mammary gland and brain homogenates used for vaccination." [38][39]
Natural transmission of scrapie in the field seems to occur via the alimentary tract in the majority of cases, and scrapie-free sheep flocks can become infected on pastures where outbreaks of scrapie had been observed before. These findings point to a sustained contagion in the environment, notably in the soil.[30]
A control flock of Swaledales has been used to study and develop scrapie-resistant sheep. An infectious, persistent, and spontaneous disease, animals infected with scrapie must be quarantined and destroyed. The experimental breeding involved selecting a group of Swaledale sheep with low suspectability to the disease, injecting them with the agents of the disease, and breeding from the survivors. The research has concluded that the offspring of the infected sheep are more able to survive scrapie.