Scrapie

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Posture (and gait disorder) in a sheep suffering from scrapie

Scrapie (from English scrape , “to scratch”, “to scrape”) or scrum disease (Paraplegia enzootica) , more rarely also Gnubber disease , Wetz disease or Rida , is a transmissible, slowly fatal disease of the brain (encephalopathy) in sheep and, to a lesser extent, goats. It is most likely caused by malformed proteins ( prions ). Scrapie is associated with the formation of cavities ( vacuolations ) in the nerve cells and manifests itself in behavioral and gait disorders. The English name comes from the fact that the sick sheep have a tendency to rub off the wool as a result of severe itching . Like Creutzfeldt-Jakob disease and Kuru in humans, it belongs to the group of communicable (transmissible) spongiform encephalopathies (TSE). Like all TSEs, scrape is a notifiable animal disease . The transfer of the pathogen to the cattle is considered to be the cause of the occurrence of BSE . In 2015 there were eleven confirmed cases of scrapie in Germany, the highest number of cases (n = 43) since 1990 was observed in 2004.

etiology

An infectious agent (scrapie agent) is a pathologically altered protein , a prion . The normal prion protein (PrP C , "c" stands for English cell = cell ) consists of 256 amino acids in sheep (in mammals the number varies between 253 and 273 amino acids). Its C-terminal (the end at which the carboxy group is not involved in a peptide bond ) domain consists of three α-helices and contains two antiparallel β-sheets . It is a component of almost all cells, especially the nerve contact points ( synapses ) in the nervous system , its function is so far unknown. The PrP gene is on chromosome 20.

The pathologically altered prion protein (PrP RES or PrP Sc , from resistant or scrapie ) differs only in a higher proportion of β-sheet structures. This makes it insoluble and no longer degradable by protein-splitting enzymes ( proteases ) (amyloidosis). The molar mass of the portion of PrP Sc produced by treatment with proteinase K is 33 to 35 kilodaltons . The pathologically altered prion proteins accumulate and form fibrils 500 to 1000 nm long (scrapie-associated fibrils, SAF) within the nerve cells. There are various sub-forms of PrP Sc (pathogen strains) that differ in terms of their protease sensitivity and pathogenic effects in the mouse model.

After the prion theory changed prion proteins even call a change also healthy PrP C out. The exact mechanism of this process is not yet known and probably host factors and play copper - ion a role in the formation. The PrP Sc of sheep, like that of BSE-infected cattle, can cause such a change in humans, but the disease-causing effect of the sheep PrP Sc on humans is many times less than that of Creutzfeldt-Jakob disease. The risk of infection for humans is therefore low, so far there have been no reliable transmissions from sheep to humans, but classification as potentially dangerous seems justified.

The PrP Sc is not only largely insensitive to degradation by cellular processes, but also to chemical and physical influences. It is largely resistant to many disinfectants , ionizing and UV radiation . Moist heat (131 ° C) in autoclaves used for sterilization in medicine only destroy the PrP Sc after two hours, so medical instruments have to be autoclaved four times in a row. In dry heat, the prion is only inactivated after 60 minutes at 200 ° C. Effective disinfectants are z. B. sodium hydroxide , guanidinium thiocyanate and sodium hypochlorite .

Virus hypothesis

Another hypothesis, which today is only supported by a few scientists, assumes an unknown virus or virus-like virion as the cause of the disease and the prion protein is only assigned a role as a receptor on the cell surface.

transmission

The pathological prion occurs in the central nervous system , cerebrospinal fluid , in tonsils , lymph nodes and in the spleen . It is excreted through the afterbirth and the amniotic fluid . Surfaces contaminated with the scrapie agent can be a source of infection for years.

The natural transmission mostly takes place through the oral ingestion of the afterbirth and amniotic fluid or water or feed contaminated with it, as well as licking the lamb by the ewe. The mother animal can transmit the disease to the fetus . Apparently transmission through contact is also possible, transmission through mites ( hay mite ) is also being discussed. The transmission of infection via the conjunctiva and the smallest injuries to the oral mucosa as well as blood transfusions has also been experimentally demonstrated. Contaminated vaccines have also been identified as triggers. Likewise, transmission through the consumption of milk and milk products by small ruminants is not excluded.

The pathogen reaches the spinal cord via the enteric nervous system and the visceral nerves and from there ascends into the brain. In sheep, spread via the lymphatic system also plays a role.

responsiveness

In principle, all sheep breeds are receptive. In addition to sheep and (to a lesser extent) goats , minks , mice , rats , hamsters , European mouflons , monkeys and humans are also susceptible. The transfer of the pathogen to cattle ( BSE ) is viewed as an independent TSE .

Susceptibility in sheep varies depending on the genetic variation in the amino acid sequence of the prion protein. Sheep with a homozygous genetic make-up for alanine (A) in position 136, arginine (R) in position 154 and arginine in position 171 (AA 136 , RR 154 , RR 171 ) are almost resistant. However, atypical cases of scrapie have also become known with this genotype and this genotype is in principle also susceptible to the BSE agent, so that the animals can be silent carriers for BSE.

Genotype class Genotype * Danger
G1 AA, RR, RR extremely low ("resistant")
G2 AA, RH, RQ
AA, RR, RH
AA, RR, RQ 		low risk when mating with G1 or G2
G3 AA, HH, QQ
AA, HR, QH
AA, HR, QQ
AA, RR, HH
AA, RR, HQ
AA, RR, QQ 		increased risk for the individual animal, the most common genotype affected in Germany is ARQ
G4 AV RR, RQ high risk for the individual and half of the offspring
G5 AV, HR, QQ
AV, RR, HQ
AV, RR, QQ
VV, RR, QQ 		very high risk
* Amino acids 136, 154 and 171 of both chromosome sets; A = alanine , R = arginine , V = valine , H = histidine , Q = glutamine ; Pairs of the same letters mean homozygosity. (Source: NSP Genotypes Table of DEFRA )

In the EU , the member states have been obliged since 2003 to set up programs for breeding sheep for resistance to TSE. This genetic dependency does not exist in goats, so that breeding on scrapie-resistant animals is not possible.

Clinical picture

According to the prion theory , the incubation period should be several (usually three to four) years. In the case of experimental infection, incubation times of 180 to 900 days were determined. Such long times until the first symptoms develop are otherwise only known in the case of chronic diseases such as the immune system , chronic poisoning or hereditary diseases. Scrape disease is one of the so-called slow infections ("slow infections"). The disease does not appear clinically until the age of 18 months at the earliest, and it occurs most frequently at the age of three. Scrape disease is a disease of individual animals, it affects up to 1% of the animals in a herd.

Damage to fleece caused by rubbing as a result of severe itching in a scrapie sheep

Clinically, the disease first shows up in behavioral changes such as jitteriness, restlessness, changes in lip ("gnubber") and ear play as well as nodding and sideways movements of the head. When grasped, sick animals suddenly collapse. Increased salivation is also often observed. Another characteristic feature are disorders of the movement processes such as a trotter- like movement of the forelegs (“scrap disease”), a houndstooth-like gait or weakness of the hind limbs, dragging of the toes over the ground, unsteady gait and buckling in the limbs. The animals are no longer able to gallop and jump. Another frequently observed characteristic is itching , which leads to the animals stamping on their limbs, gnawing themselves or rubbing against objects (hence the name scrapie ), which leads to damage to the fleece . As a rule, the disease is accompanied by emaciation.

After the first symptoms of the disease, the affected sheep only survive one to six months (in extreme cases two weeks to six months), after which death inevitably occurs.

pathology

With the naked eye (macroscopically) no changes can be seen in dead animals, apart from possible skin and fleece damage as a result of chafing.

The brain tissue is histologically a cell proliferation of astroglial and then vacuolation and degeneration of nerve cells in the brain stem and cerebellum . In some cases, eosinophilic granules and shrunken ( pyknotic ) cell nuclei can be detected in the nerve cells. Vacuolization also occurs in the white matter . The scrapie-associated fibrils can be detected by electron microscopy , and the pathological prion proteins can also be detected immunohistochemically .

Diagnosis and differential diagnosis

The diagnosis can only be made with certainty on the basis of biopsies of the lymph nodes with detection of PrP Sc by ELISA or Western blot and, after death, by a pathohistological examination. In recent times, PrP Sc detection methods have also been developed in living animals before clinical symptoms appear, although these are still in the experimental stage. The diagnosis can only be made by an official veterinarian . After a positive result in an approved testing facility, a second checking examination of the sample is carried out at the Friedrich-Loeffler-Institut . Various genetic tests exist for genotyping and thus risk assessment .

Other central nervous diseases of sheep such as Bornash disease , rabies , Visna , listeriosis , coenurosis , enzootic ataxia and cerebrocortical necrosis as well as metabolic diseases associated with neurological symptoms such as ketosis and hypocalcemia must be excluded from the differential diagnosis ( see also VETAMIN D ). Regarding the itching is also a Psoroptes - mange to consider.

Combat

Since scrape disease cannot be treated, control is aimed at killing and harmlessly disposing of sick animals in affected herds, breeding for genetically resistant sheep and quarantine measures. The specific control measures are handled differently internationally.

In the European Union , control is carried out by Regulation (EC) No. 999/2001, most recently amended in Regulation (EC) No. 339/2006, and the national animal disease law (in Germany: Animal Disease Act , Animal Transport Regulation , Regulation on notifiable animal diseases and the TSE Monitoring Ordinance ; in Austria : Scrapie Monitoring Ordinance). All deaths in sheep over 18 months old must be examined for scrapie, as must all slaughter animals from this age onwards. Since scrape disease is notifiable, the appropriate measures are determined by the official veterinarian . The current regulations make it possible that no longer whole herds, but only genetic risk groups (goats G2 – G5, female sheep G3 – G5) are killed in affected herds. After herds have been killed, herds may only be filled with homozygous ARH animals or heterozygous ARH combinations with genotypes other than VRQ. The purchases should only be made from herds in which no more cases of scrapie have occurred for at least 5, better 8 years. If no appropriate animals are available, the veterinary office can issue exceptions. However, breeding on “genetically resistant” sheep has recently become questionable again due to the atypical cases of scrapie. Through consistent hygiene measures, scrapie-free stocks can also be generated with genetically susceptible genotype classes.

history

The first published scrapie case comes from Great Britain in 1732 . The number of animals sick each year is estimated at around 10,000 there alone. The disease has also occurred in Germany and the rest of Europe since the middle of the 18th century. The introduction probably took place via imports of breeding sheep. Scrape disease is now common worldwide , with the exception of Australia and New Zealand , and is most common in the UK and Cyprus .

The number of clinical illnesses in Germany decreased significantly from 1945, also due to the change in the usage concept (meat instead of wool production), since sheep today rarely get older than five years.

In 1947 there were first deaths of mink in the United States after being fed with sheep slaughterhouse waste, and from 1967 also in Europe. In 1967 it was recognized that the pathogen did not contain any nucleic acid due to its resistance to radiation and it was assumed that an infectious protein is involved. In 1982 Stanley Prusiner put forward the hypothesis of the sole protein cause of TSE, he also coined the term “prion” from proteinaceous infectious particle (“protein-like infectious particle”).

The 1985 BSE outbreak in Great Britain is attributed to the feeding of carcass meal from sheep to cattle.

See also

literature

  • H. Behrens et al. a .: Textbook of Sheep Diseases. 4th edition. Paul Parey, 2001, ISBN 3-8263-3186-9 .

Web links

Commons : Scrapie  - collection of images, videos and audio files

Individual evidence

  1. ↑ BMLV: Number of confirmed cases of scrapie in sheep and goats in Germany in 2015
  2. ↑ R. Riek et al.: NMR characterization of the full-length recombinant murine prion protein, mPrP (23-231). In: FEBS Lett . 1997 Aug 18; 413 (2), pp. 282-288. PMID 9280298
  3. ↑ KM Pan et al .: Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. In: Proc Natl Acad Sci USA . 1993 Dec 1; 90 (23), pp. 10962-10966. PMID 7902575 .
  4. ^ ME Bruce: TSE strain variation. In: Br Med Bull. 2003; 66, pp. 99-108. PMID 14522852 .
  5. ↑ C. Fasano et al.: Prions: protein only or something more? Overview of potential prion cofactors. In: J Mol Neurosci. 2006; 29 (3), pp. 195-214. PMID 17085779
  6. ^ E. Wong et al .: Copper induces increased beta-sheet content in the scrapie-susceptible ovine prion protein PrPVRQ compared with the resistant allelic variant PrPARR. In: Biochem J. 2004 May 15; 380 (Pt 1), pp. 273-282. PMID 14969585
  7. ↑ H. Cassard, JM Torres et al. a .: Evidence for zoonotic potential of ovine scrapie prions. In: Nature Communications . Volume 5, December 2014, p. 5821, doi : 10.1038 / ncomms6821 , PMID 25510416 .
  8. ↑ EE Comoy, J. Mikol et al. a .: Transmission of scrapie prions to primate after an extended silent incubation period. In: Scientific Reports . Volume 5, June 2015, p. 11573, doi : 10.1038 / srep11573 , PMID 26123044 , PMC 4485159 (free full text).
  9. ^ P. Brown et al .: Newer data on the inactivation of scrapie virus or Creutzfeldt-Jakob disease virus in brain tissue. In: J Infect Dis . 1986 Jun; 153 (6), pp. 1145-1148. PMID 3084671
  10. ↑ L. Manuelidis: Transmissible encephalopathies: speculations and realities. In: Viral Immunol. 2003; 16 (2), pp. 123-139. PMID 12828865
  11. ↑ L. Manuelidis: A 25 nm virion is the likely cause of transmissible spongiform encephalopathies. In: Cell Biochem. 2006 Oct 16. PMID 17044041
  12. ↑ EFSA Scientific Opinion: Opinion of the Panel on Biological Hazards (BIOHAZ) on the risk to humans and animals with regard to Transmissible Spongiform Encephalopathy. Efsa.europa.eu, November 6, 2008, accessed May 24, 2010 .
  13. ^ GC Saunders et al.: PrP genotypes of atypical scrapie cases in Great Britain. In: J Gen Virol. 2006 Nov; 87 (Pt 11), pp. 3141-3149. PMID 17030846
  14. ^ F. Ronzon et al.: BSE inoculation to prion diseases-resistant sheep reveals tricky silent carriers. In: Biochem Biophys Res Commun . 2006 Dec 1; 350 (4), pp. 872-877. Epub 2006 Oct 4. PMID 17049491
  15. ↑ P. Saa et al.: Detection of prions in blood. In: Nat Med . 2005 Sep; 11 (9), pp. 982-985. Epub 2005 Aug 28. PMID 16127436
  16. ^ R. Jackman et al .: Evaluation of a preclinical blood test for scrapie in sheep using immunocapillary electrophoresis. In: Journal of AOAC International . 2006; 89 (3), pp. 720-727. PMID 16792071 .
  17. ^ Text of the TSE Monitoring Ordinance
  18. ↑ Scrapie Monitoring Ordinance Austria (PDF)
  19. ↑ A. Buschmann, MH Groschup: TSE control in small ruminants - quo vadis? In: Berl Munch Tierarztl Wochenschr. 2005 Sep-Oct; 118 (9-10), pp. 365-371. PMID 16206923
  20. ↑ J. Foster et al.: Derivation of a scrapie-free sheep flock from the progeny of a flock affected by scrapie. In: Vet Rec. 2006 Jul 8; 159 (2), pp. 42-45. PMID 16829598
This version was added to the list of articles worth reading on November 23, 2006 .