Scrapie

Ewe with scrapie with weight loss and hunched appearance

Same ewe as above with bare patches on rear end from scraping

Scrapie is a fatal, degenerative disease that affects the nervous systems of sheep and goats. It is one of several transmissible spongiform encephalopathies (TSEs), which are related to bovine spongiform encephalopathy (BSE or "mad cow disease") and chronic wasting disease of deer. Like other spongiform encephalopathies, scrapie is caused by a prion. Scrapie has been known since the 18th century (1732) and does not appear to be transmissible to humans.

The name scrapie is derived from one of the clinical signs of the condition, wherein affected animals will compulsively scrape off their fleece 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.

Scrapie is infectious and transmissible among similar animals, and so one of the most common ways to contain scrapie (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 that prions may be spread through urine and persist in the environment for decades.

Scrapie usually affects sheep around 3–5 years of age. There appears to be the potential for transmission at birth and from contact with placental tissues. There is no evidence that scrapie is infectious to humans.

Uptake of prions

Lymph nodes from (a) healthy and (b) infected sheep. Colouring with antibodies shows clear sign of scrapie prions in the intracellular tissue of the infected sheep.

The protein enters through the intestines or through cuts in the skin. The prions cause normal proteins of the sheep to fold into the wrong shape. These proteins are gradually accumulated in the body, especially in nerve cells which subsequently die. When the prions are absorbed through the intestines, they first appear in the lymph nodes, especially in Peyer's patches at the small intestine.

An experiment has shown that lambs risk being infected through milk from infected ewes. But the lambs in the experiment also infected each other, making it difficult to assess the risk of infection. The experiment did not continue long enough to show that the lambs developed symptoms, merely that the prion was present in the body.

Clinical signs and diagnosis

Changes are mild at first, there may be slight behavioural changes and maybe an increase in chewing movements. Ataxia and neurological signs then develop, and affected sheep struggle to keep up with the flock.

Some sheep scratch excessively and will show patches of wool loss and lesions on the skin. Scratching sheep over the rump area may lead to a nibbling reflex which is pathognomonic for the condition.

Signs that this is a chronic systemic disease appear later, with weight loss, anorexia, lethargy and possibly death.

Post-mortem examination is important for the diagnosis of scrapie. Histology of tissues will show accumulation of prion in the central nervous system and immunohistochemical staining and ELISA can also be used to demonstrate the protein. Sampling the third eyelid lymphoid tissue is also possible.

Treatment and preventive action

No treatment is available for affected sheep.

A test is now available which is performed by sampling a small amount of lymphatic tissue from the third eyelid.

In the United Kingdom, the government has put in place a National Scrapie Plan, which encourages breeding from sheep that are genetically more resistant to scrapie. It is intended that this will eventually reduce the incidence of the disease in the UK sheep population. Scrapie occurs in Europe and North America, but to date Australia and New Zealand (both major sheep-producing countries) are scrapie-free.

Breeds such as cheviot sheep and suffolk are more susceptible to scrapie than other breeds. Specifically, this is determined by the genes coding for the naturally occurring prion proteins. The most resistant sheep have a double set of "ARR" alleles, while sheep with the "VRQ" allele are the most susceptible. A simple blood test reveals the allele of the sheep and many countries are actively breeding away the VRQ allele.

Out of fear of BSE, many European countries banned some traditional sheep or goat products made without removing the spinal cord such as smalahove and smokie.

In 2010, A team from New York described detection of PrP^Sc even when initially present at only one part in a hundred thousand million (10⁻¹¹) in brain tissue. The method combines amplification with a novel technology called Surround Optical Fiber Immunoassay (SOFIA) and some specific antibodies against PrP^Sc. After amplifying and then concentrating any PrP^Sc, the samples are labelled with a fluorescent dye using an antibody for specificity and then finally loaded into a micro-capillary tube. This tube is placed in a specially constructed apparatus so that it is totally surrounded by optical fibres to capture all light emitted once the dye is excited using a laser. The technique allowed detection of PrP^Sc 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. The researchers 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 PrP^Sc 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.

Transmission/Exposure Pathways

Various studies have indicated that prions (PrP^SC) that infect sheep and goats with the fatal transmissible encephalopathy known as scrapie, are able to persist in soil for years without losing their pathogenic activity. Dissemination of prions into the environment can occur from several sources: mainly, infectious placenta or amniotic fluid of sheep and possibly environmental contamination by saliva or excrements.

Confirmatory tesing for scrapie can only be achieved by applying Immunohistochemistry (IHC) of disease-associated prion protein (PrP^Sc) to tissues collected postmortem, including obex, retropharyngeal lymph node and palatine tonsil. A live animal diagnostic, not confirmatory, test was approved in 2008 for immunochemistry testing on rectal biopsy-derived lymphoid tissue by USDA.

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, and notably the soil.

Prion concentration in birth fluids does not alter the infectivity of the prions. Even when placentas have little PrPS^C (Prion protein - scrapie), kids born to naturally or experimentally infected does become infected themselves. PrP^SC are shed at a higher percent, 52%- 72% in in sheep placentas then goat placenta at 5-10% in study trials at the USDA Agricultural Research Service by Dr. O’Rourke.

Fecal concentration of PrP^SC has been reported in the feces of sheep both in the terminal and the early preclinical stages of the disease suggesting that prions are likely to be shed into the environment throughout the pathogenesis. Several sources of prions in feces could be postulated including environmental ingestion and swallowing infected saliva however the most likely source is shedding from the gut-associated lymphoid tissue. Ruminants have specialized Peyer's patches that throughout the length of the ileum amount to approximately 100,000 follicles and all of these could be infected and shedding prions in to the lumen. Scrapie prions have been found in the Peyer's patches of naturally infected nonclinical lambs as young as 4 months of age.

Exposure through contaminated soil via placentas or feces

Ingestion of soil by grazing sheep has been measured in two soil types, at two stocking rates and over two grazing seasons. Animals ingested up to 44g soil per kg of body weight between May and November. Rainfall and stocking rate emerged as factors influencing ingestion. The effect of soil type and herbage on offer was less evident.

The average weight of an adult sheep is aproximately 250 pounds. If an adult sheep ate 400g/kg of soil as predicted by D. McGrath et al. then the average sheep would ingest approximately 45,000 g over 6 months or 251g per day. Assuming the soil was contaminated with prions (PrP^SC) from feces or birth fluids then potentially the sheep would be infected. The concentration of the prions is uncertain however as concentration is not directly proportionate to infectivity.

Factors affecting Prion infectivity in the soil: Factors affecting prion infectivity in the soil have been shown to include the length of time in the soil and the binding abilities of the soil.

'Length of time': For a detailed risk assessment of scrapie-contaminated soil it was of major importance to analyze whether the detectable PrP^Sc 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 first scrapie- associated symptoms at 2 weeks to 6 months (95% CI)after the first application. The hamsters reached the terminal stage of scrapie at 5 to 21 months (95% CI) after the first feeding. This indicates substantial amounts of persistent infectivity in soil that had been incubated for 26 and 29 months. In Iceland, in 1978, a program was implemented to eradicate scrapie and affected flocks were culled, premises were disinfected, sheep houses were burnt and after 2-3 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 environmental contamination.

'Soil types' : the binding abilities of different soil types have been shown to enhance disease penetrance. Soil containing the common clay mineral montmorillonite (Mte) and kaolinite (Kte) binds more effectively with the prions (PrP^SC) than soil that contains quartz. Enhanced transmissibility of soil-bound prions may explain the environmental spread of scrapie despite low levels shed into the environment. The mechanism by which Mte or other soil components enhances the transmissibility of particle bound prions remains to be clarified. Prion binding to Mte or other soil components may partially protect PrP^SC from denaturation or proteolysis in the digestive tract allowing more disease agent to be taken up from the gut. Adsorption of PrP^Sc soil may alter aggregation state of the protein, shifting the size distribution toward more infectious prion protein particles thereby increasing the infectious units. For prion disease to be transmitted via ingestion of prion contaminated soil, prions must also remain infectious by the oral route of exposure. Researchers at the University of Wisconsin investigated the oral infectivity of Mte and soil bound prions. The effects of prion source (via infected brain homogenate and purified PrP^Sc) and dose on penetrance (proportion of animals eventually exhibiting clinical signs of scrapie) and incubation period (time to onset of clinical symptoms) was evaluated. Approximately 38% of animals receiving 200ng of unbound clarified PrP^Sc orally exhibited clinical symptoms with an incubation period for infected animals of 203 to 633 days. In contrast, all animals orally dosed with an equivalent amount of Mte-bound PrP^Sc manifested disease symptoms in 195 to 637 days. Animals orally receiving Mte soil alone or 10-fold less unbound clarified PrP^Sc (20ng) remained asymptomatic throughout the course of the experiment. These data established that the Mte-bound prions remain infectious via the oral route of exposure but that the agent binding Mte increases disease penetrance, enhancing the efficiency of oral transmission.

Transmission Summary

Prions (PrP^Sc) are shed from sheep and goats in birth fluids, feces and other excrements. The concentration of the prions is uncertain however it is not directly proportionate to infectivity. Sheep do ingest soil and therefore soil represents a plausible environmental reservoir of scrapie which can persist in the environment for years. Longevity of the prions and the attachment of soil particles likely influences the persistence and infectivity of prions in the environment. Effective methods to inactivate prions in the soil are currently lacking and the effects of natural degradation mechanisms on prion infectivity are largely unknown. An improved understanding of the processes affecting the mobility, persistence and bioavailability of prions in soil is needed for the management of prion contaminated environments. A system for estimating the prion binding capacity of soil on US farms using simple soil analysis may give us an estimate of the prion risk in the environment and if prion binding is likely possibly the use of soil amendments or top dressings may help to mitigate the infectious prions. Lichens, Lobaria pulmonaria, may have potential for reducing the number of prions because some lichen species contain a protease enzyme that show promise in breaking down the prion. Further work to clone and characterize the protease, assess its effects on prion infectivity and determine which organism or organisms present in lichens produce or influence the protease activity is warranted and is currently under investigation.

See also

• Kuru
• Transmissible mink encephalopathy
• Creutzfeldt-Jakob disease

External links

• Article about scrapie and the aforementioned diagnostic test
• UK government scrapie information
• UK government National Scrapie Plan
• Scrapie research at the Institute for Animal Health (UK)
• Sheep genetics research at the Institute for Animal Health (includes photo of a sheep with scrapie)
• Scrapie in the United States
• US Department of Agriculture video of infected sheep demonstrating Hopping Gait