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Introduction and General Information

  • The prion diseases or transmissible spongiform encephalopathies (TSEs) are a group of diseases in humans and animals that share certain characteristics:
    • A long incubation or latent period;
    • Lack of response to treatment;
    • Progressive clinical disease with a consistent fatal outcome;
    • The transmissible spongiform encephalopathies (TSEs) are so called because they show similar histopathological lesions in the CNS, typically including neuronal vacuolation (i.e. the brain tissue has "holes" and looks "spongy"), neuronal cell death, and gliosis, as well as accumulation of an abnormal form of prion protein. 
    • (J234.14.w1)
  • A number of natural prion diseases have been detected:
    • In Cervidae (elk and deer): chronic wasting disease (CWD) (origin unknown);
    • In humans: Creutzfeldt-Jakob Disease (CJD) (sporadic, familial and iatrogenic), kuru (transmitted by ritual cannibalism), GSS (familial), FFI (familial) and new variant CJD (nvCJD or vCJD) (from BSE);
    • In sheep, goats and mouflon: scrapie;
    • In cattle: BSE (bovine spongiform encephalopathy, also known as "mad cow disease" (also seen in various ruminants of the family bovidae in zoos);
    • In cats: FSE (feline spongiform encephalopathy, considered to be derived from BSE, this has been seen in domestic cats and in various other felidae in zoos);
    • In mink: transmissible mink encephalopathy (TME) (origin unknown).
  • The TSEs have been shown to be transmissible from one animal to another experimentally and some of the diseases are known to be naturally transmissible.
  • The various prion diseases are transmissible experimentally (by inoculation into experimental animals) but their normal routes of transmission vary:
    • CWD of deer and elk, and scrapie of sheep and goats, appear to be transmitted from one living animal to another. This transmission may be direct or indirect (i.e. the agent passes from an affected animal into the environment and is then taken up by another individual). It is probable that the agent is taken up orally but possibly also through breaks in the skin (cuts, scratches or sores).
    • TME of mink, kuru of humans, BSE of cattle and other bovidae, FSE of cats and nvCJD of humans appear to be transmitted orally by ingestion of food contaminated with the agent. It is possible that the agent may also be taken up through breaks in the skin or mucous membranes (cuts, scratches or sores).
    • Some of the diseases in humans are familial, associated with a change in the gene responsible for production of the protein PrP.
    • Some cases in humans are iatrogenic, caused by accidental inoculation of material from an affected person into a new person. Scrapie has also occurred following iatrogenic transmission in contaminated vaccine.
    • Some cases of CJD in humans are sporadic: that is they occur for no known reason.
  • These diseases are known to be associated with an abnormal form (PrPres or PrPSc) of a normal cellular protein (PrPsen or PrPC).
  • There are still uncertainties about the agent that causes TSEs. 
    • Various experiments looking at the nature of the infectious agent have indicated that it is not a conventional virus and may not even contain any nucleic acid (DNA or RNA). 
    • The hypothesis most widely accepted at present is that the abnormal prion protein is itself the agent (J22.216.w1), possibly in association with another factor (protein X) which has not yet been identified.
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Normal Prions and Abnormal Prions
The hallmark of prion diseases is the accumulation of an abnormal isoform (PrPSc) of a normal protein (PrPC) that is highly conserved in all mammalian species. (J248.2.w1)
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Conversion of Normal Prions to Abnormal Prions
Conversion of PrPC to PrPSc does not involve any change in the primary structure (the amino acid sequence) of the protein. Rather it involves a change in the way in which the protein structure is folded.
  • The normal cellular protein PrPC, which has a predominantly alpha-helical conformation, is converted, post-translationally, into the beta-pleated sheet structure of PrPSc. (D108)
  • It appears that the abnormally folded PrPSc aggregates (sticks together) and that this aggregated PrPSc is able to act as a catalyst to change PrPC into more PrPSc.
  • The most commonly accepted hypothesis at the present time is that the agent causing the TSEs is a proteinaceous infectious particle lacking nucleic acids and that PrPSc is the main, or only, molecule involved. However it is possible that another component is an essential part of the infectious particle. (J135.95.w1)
  • It appears that conversion of PrPC to PrPSc, in addition to requiring the presence of PrPSc, involves another protein, designated "Protein X". (J135.94.w2)
  • See:
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Pathology (Cellular damage)
PrPSc can accumulate in a variety of tissues within the body, such as in lymphoid tissues. However pathological changes in tissues occur only in the central nervous system (CNS).
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Theories about the agent 
(See: CWD Literature Reports: Aetiology (Disease Reports) - Theories on the nature of the causative Agent of the TSE diseases  for the data sources, including evidence for and against each theory and details of less recognised theories.)

Protein-only Theory

  • At the present time the "protein-only" theory is the theory most widely accepted for the development of TSEs.
  • This theory suggests that the protease-resistant abnormal form of PrP, generally referred to as PrPSc or PrPres, is the infective agent required for the conversion of normal cellular PrPC to the abnormal form and development of disease.
  • Recent developments of this theory include a requirement for an additional factor, "protein X", for the conversion to occur in the host individual, but not the presence of any nucleic acid from outside the host.
  • This theory would explain the lack of an immune response to the agent, hereditary forms of TSE in humans and the fact that infectivity copurifies with PrP.
  • However, the existence of distinct strains of the agent, and the separation of PrPSc production from infectivity in certain cases, have not been fully explained by this theory. 
  • To date it has not been possible to convert PrPC into PrPSc in vitro and show that the newly converted protein is infective.

This theory is not accepted by all scientists working in this field. A variety of other theories have been suggested. Some are proposed only by one person or one team of researchers.

Unconventional virus theory 

  • This theory suggests that the agent of TSEs is a virus, if an unconventional one.
  • Proponents of this theory suggest that a virus agent would most clearly explain the presence of different "strains" of the TSE agent.
  • While no virus has been identified and some data indicated that the agent does not respond to e.g. radiation in a way expected by viruses, other researchers note that unknown viruses can be difficult to isolate and consider that data on size and inactivation studies is not incompatible with the presence of a virus.

(J22.197.w1, B297.1.w1, B302)

Virino theory

  • This theory suggests that the infectious agent is a small, noncoding, regulatory nucleic acid surrounded and protected by a host-coded protein.
  • It is suggested that the unconventional nature of the agent is due to the fact that the nucleic acid is so well protected by its association with host protein.
  • This theory would account for strains of the agent.

(B293.w3, D108, D132, J9.391.w1) 

Nemavirus theory

  • This theory suggests that the TSE agent has a three-layer structure with an inner core of PrP/SAF (scrapie associated fibril), with ss-DNA (single-stranded DNA) coiled around this and an outer layer of protein surrounding this. It is suggested that the ss-DNA codes for a protein which, by interacting with normal cellular PrP or with the host PrP gene, results in a post-translational modification of PrPC to PrPSc. (J266.34.w1, J124.149.w1)
  • The resistance of the agent to agents which would disrupt nucleic acids is considered to be due to the unusual three-layer structure and to the palindromic repeat coding of the ss-DNA. (J266.34.w1, J124.149.w1)
  • Work to isolate the ss-DNA has not been repeatable by independent researchers. (J223.7.w3)

Spiroplasma theory

  • This theory suggests that the aetiological agents of the TSEs are spiroplasmas, unusual prokaryotes. (J93.25.w1, J271.60.w1)

For further information and references regarding these theories see: CWD Literature Reports- Aetiology (Disease Reports) - Theories on the nature of the causative Agent of the TSE diseases

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Transmission between hosts
The normal route of transmission for the TSEs is thought to be oral. In natural disease PrPSc can be detected in lymphoid tissues associated with the alimentary tract before it is detected in nervous tissues and the CNS.

In CWD the disease is known to be transmitted between animals (lateral transmission) and this is thought probably to be by the oral route. 

How the agent leaves the host:

  • Since PrPCWD can be found in lymphoid tissues associated with the alimentary tract from relatively early in the course of infection it is possible that secretions and excretions such as saliva and faeces may act as sources of the infectious agent for other animals to take in orally. 
  • In scrapie of sheep and goats the placenta (afterbirth) may act as a source of infectious agent for other animals.
  • In BSE and the related diseases FSE and nvCJD, as well as in TME, there is strong epidemiological evidence that the source of infection is contaminated food.
  • In the human disease kuru, ritual cannibalism was the means of transmission.
  • It is possible that urine may be a source of infectious agent. 
    • A protease-resistant isoform of prion protein has been found in the urine of some animals and humans with prion diseases although the form which was isolated was not shown capable of transmitting disease. (J236.276.w1)

How/Where the agent enters the new host:

  • Entry into a new host in natural infection is probably usually by the agent being taken in orally. 
  • It is possible that the agent can enter the animal through superficial wounds (e.g. scratches or abrasions) within the mouth or on the skin.

How the agent is transported to the CNS:

See: Prion Protein Literature Reports: Transmission (Chemical Reports)

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How cellular damage is caused
  • In the prion diseases histopathological changes have been observed only in the CNS. (J248.2.w1)
  • Three types of change have been describes which are visible by light and electron microscopy: astrocytosis, microglial proliferation and neuronal cell death by apoptosis. At this time we do not understand why these occur or whether any of these changes is related to the other changes. 
See: Prion Protein Literature Reports: Cellular Reactions (Chemical Reports)
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Interaction with host genetics
Within species
  • In elk (Cervus elaphus nelsoni - Rocky Mountain Elk (Cervus elaphus - Red deer)) there appear to be some genetic differences in susceptibility to CWD; individuals homozygous for methionine at PrP cervid codon 132 were over-represented among individuals with CWD when compared to unaffected individuals. However it is not possible at this stage to say whether any genetic variants are totally resistant to CWD.
  • In white-tailed deer (Odocoileus virginianus - White-tailed deer) in Wisconsin the QGS allele tended to be over-represented in CWD-positive deer but CWD-positives were found in individuals of all PrP genotypes. 
  • The influence of host genetics on development of TSEs has been studied extensively in sheep and mice. 
    • In mice the Sinc ( Scrapie incubation period) gene, now known to be same as the PrP gene, Prnp, controls the incubation period following scrapie inoculation.
    • In sheep amino acid polymorphisms have been described at seven codons within the PrP gene. Polymorphisms at three of these sites, codons 136 (valine or alanine), 171 (glutamine or arginine) and to a lesser extent 154 (histidine or arginine) are associated with susceptibility to scrapie and also affect susceptibility to BSE.
  • Two PrP alleles are recognised in cattle but there does not appear to be any genetic influence on susceptibility to BSE in this species.
  • In humans some cases of prion diseases (familial Creutzfeldt-Jakob Disease (familial CJD), Fatal Familial Insomnia (FFI) and Gersmann-Staussler-Scheinker disease (GSS)) are inherited genetic diseases associated with particular mutations of the PrP gene. 
  • Homozygosity at codon129 of the human PrP gene appears to make people more susceptible to sporadic CJD, iatrogenic CJD and new-variant CJD.

Between species

  • In general transmission of prion agents from one species to another occurs less easily than transmission from one individual to another individual of the same species. This is sometimes known as the "species barrier" effect.
  • It is thought that this is related to differences in the precise amino acid sequence of PrP between species, with PrPSc converting PrPC of the same specis more easily than it converts PrPC from a different species.
  • There may also be an effect of species specificity of the unidentified additional factor, sometimes called protein X, which is thought to facilitate the PrPC to PrPSc conversion.

See: CWD Literature Reports: Susceptibility Factors (Concurrent Disease, Immunosupression) (Disease Reports)

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Further research

There are many aspects of prions and prion diseases that are as yet understood only poorly, or are not understood at all. 

Questions which require answers include:

  • Confirmation of the agent responsible for these diseases.
  • How the different stains arise if the agent is only a protein.
  • How the damage is caused to the central nervous system.

For effective management of CWD it will be necessary to develop a better understanding of the biology and pathology of CWD, including:

  • The pathogenesis of CWD; 
  • Whether different strains of CWD infect different cervids;
  • Which species are susceptible to CWD, including cattle; 
  • The routes of exposure of CWD;
  • The rate of transmission of CWD;
  • The amount of CWD agent needed to cause infection; 
  • The contribution of genetics to CWD susceptibility among cervid populations;
  • Development of prophylactic or treatment measures for both captive and free-ranging susceptible cervids.

(D110)

N.B. Results of research must be distributed effectively if they are to be of benefit to agencies responsible for disease management.

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Authors & Referees

Authors Dr Debra Bourne MA VetMB PhD MRCVS (V.w5)
Referee Suzanne I Boardman BVMS MRCVS (V.w6), Chris Brand (V.w52), Dr Terry Kreeger (V.w49), Dr Julie Langenberg (V.w50), Bruce Morrison (V.w48), Michael Samuel (V.w53), Scott Wright (V.w54)

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