Diseases / Miscellaneous / Multi-factorial / Metabolic Diseases / Chronic Wasting Disease of Deer and Elk / Detailed Disease Description:

< > Literature Reports of AETIOLOGY of CWD of Deer and Elk:


Editorial Summary (Editorial Overview Text Replicated on Overall Disease page - CWD of Deer and Elk)
  • The weight of scientific evidence indicates that the infectious agent of CWD is an aberrant form of a normal protein in the brain (PrP): this aberrant protein (PrPres) becomes resistant to natural breakdown by enzymes and builds up in the brain cells.
  • The origin of CWD is unknown and is unlikely to be determined. It is possible that it represents either a form of scrapie which has become adapted to cervids or a spontaneously arising spongiform encephalopathy of cervids, or even transmission to cervids of a TSE strain from an unknown source.
  • Unlike BSE no link has been identified with feeding animal protein to cervids. 
  • It is clear from transmission experiments that the disease is caused by a transmissible agent.
  • It is not known how long the disease has been present in deer and elk populations in the USA. Cases have been recognised in captive wildlife facilities since the 1960s.
  • In addition to the aberrant PrP theory, there are a number of other theories associated with the process of the development of the Transmissible Spongiform Encephalopathies. For the sake of completeness, these are also discussed below, and include:
    • Protein-only theory
    • Unconventional virus theory
    • Virino theory
    • Nemavirus theory
    • Spiroplasma theory
    • Autoimmune theory
    • Organophosphate theory
    • Manganese excess / Copper deficiency theory

Limited data on other TSE diseases is provided in literature reports below the information on CWD. Information on these diseases within the "Chronic Wasting Disease of Deer and Elk" volume of Wildpro is provided for comparative purposes and is not intended to be comprehensive.

The literature reports below are subdivided into the following sections:

Source Information CWD of Deer and Elk
  • CWD is caused by an infectious agent. This has been demonstrated by transmissible of the disease via intracerebral inoculation of brain tissue from infected individuals into other individuals, including both species known to be naturally susceptible (Odocoileus hemionus - Mule deer) and species not known to be naturally susceptible (domestic ferrets Mustela putorius fero (Mustela putorius - Polecat), squirrel monkeys Saimiri sciurius (Cebidae - New-world monkeys (Family)) and one Capra hircus - Domestic goat). (J64.11.w3)
  • It is possible that the disease was brought into the captive wildlife research facilities from the wild by one or a few infected individuals which then, under the conditions of close confinement, transmitted the agent to other cervids. (J64.11.w3)
  • The origin of CWD is unknown. Possibilities for routes into captive wildlife research facilities include transmission from infected but undiagnosed sheep or goats with scrapie, or that the disease was brought into the facilities with one or more individual cervids latently infected when taken from the wild. Concentration (close confinement, high population density) within the facilities may then have facilitated transmission of the agent to other individuals. (P42.12.w1)
  • It is possible that CWD is a strain of scrapie which has become adapted to cervids but there is no clear evidence that CWD arose from contact with sheep. (J195.17.w1)
  • The source of CWD in free-ranging cervids in North America is undetermined and may represent a spontaneous naturally occurring spongiform encephalopathy of cervids, or may be a "spill-over" of scrapie from domestic sheep. (B293.w1)
  • There is no known association of CWD with feeding animal protein to mule deer. No animal protein other than milk (raw or pasteurised whole milk, canned evaporated milk, buttermilk or commercial lamb milk replacer) known to have been fed to affected captive animals in wildlife research facilities. (J64.11.w3)
  • "The origins and mode of transmission of CWD remain unclear. It is also unknown whether there are different strains of CWD prions or whether CWD poses a risk to other animals or humans." (P40.1.w2)
  • "There is a critical gap in understanding the origins of CWD." It is possible that CWD developed from scrapie at some time in the more than 400 years that sheep have been present in the New World. Cases of disease in cervids with clinical signs compatible with CWD have occurred historically and it is possible that it has simply not been diagnosed since histological examination of the brain stem was not undertaken. (P40.1.w46)
  • It is possible that CWD arose from a spontaneous somatic mutation of the PRNP gene in mule deer, followed by transmission to elk and white-tailed deer, or that it originated from a strain of scrapie which became adapted to cervids, or even that it originated from infection of cervids with an as yet unrecognised prion strain from an unknown source. (J64.21.w17)
  • To date, while the natural rate of expansion in free-ranging cervid populations has been slow, it appears that the disease has been spread much more widely by the movement of infected farmed elk. In at least three areas (west-central Saskatchewan, northwest Nebraska and southwest South Dakota) it is possible that an elk farm infected with CWD may have acted as a source of infection for the local populations of free-ranging cervids. (J40.66.w1)
  • In captive wildlife research facilities in Colorado and Wyoming, detection of CWD in elk followed detection in mule deer by about two years. It was suggested that, if the incubation period in the two species is taken to be similar, then the mule deer transmitted the disease to the elk. (J64.11.w3)

  • In game farms in Saskatchewan, Canada, all infected premises were shown to be linked to one premises which was believed to have become infected by import of elk from the USA. (W43.10Apr03.CWD4)

Aetiology of the other TSE Diseases

Transmissible Mink Encephalopathy:

Mustela vison - American mink:

  • TME is considered to be a food-borne infection. (J100.115.w1)
  • Data from an outbreak in Ontario, USA in 1963 found no evidence of exposure to sheep or sheep by-products although the possibility of occasional inclusion of trimmings from sheep carcasses in slaughterhouse products fed to mink could not be ruled out. [1968](J14.9.w1)
  • Investigations following an outbreak on two farms in Wisconsin found that "downer" cows had been fed at the presumed time of infection. It was however not possible to eliminate the possibility that parts from sheep or other carcasses had been part of the meat shipments. [1965](J100.115.w1)
  • In only one of 14 outbreaks of TME worldwide was a there a possible link to scrapie: an outbreak in Finland occurred on a farm which was the only one in the area to feed sheep heads. (B292.w20)
  • Mink inoculated with strains of scrapie from the USA developed typical clinical signs of TME, however incubation periods following even intracranial inoculation were longer than those suggested for natural TME outbreaks and oral exposure did not result in disease after as long as two years. (B292.w20)
  • Following two passages in goats by intracerebral inoculation the agent was still nonpathogenic for mice, nevertheless the results of the study were considered compatible with the agent being a form of scrapie altered due to passage through mink. (J240.51.w1)
  • Mink in the "Stetsonville" outbreak of TME had never been fed sheep products but were fed large quantities of products from fallen and sick dairy cattle. [1991] (J223.72.w1)
  • With the Stetsonville source of TME, there was no evidence of deadaptation to mink following passage through cattle; infected cattle brain passaged back to mink was highly pathogenic by the intracerebral or oral routes. Results were suggested to indicate the presence of an unrecognised, scrapie-like disease in cattle in the USA. [1991](J223.72.w1)
  • Testing of mink with known sources of scrapie agent has not succeeded in transmistting disease by the oral route. (J223.72.w1)
  • "There is no definite association between the occurrence of TME and feeding sheep tissues to mink." For at least two incidents the mink rancher stated "with a high degree of certainty" that dead sheep had not been fed to the affected mink. "If TME results from feeding infected cattle tissues to mink, there must be an unrecognised BSE-like infection in American cattle and in other countries where TME has been reported. This hypothetical agent need not have biological properties identical to those of the BSE agent because it is likely that cattle could be infected with several "strains" as are sheep." [1992] (J64.11.w5)
  • Following the Stetsonville incident of TME, in which the mink had been fed 'downer cows' but not sheep, it was found that the agent produced a fatal spongiform encephalopathy when inoculated intracerebrally into cattle and could be passed back to mink, by the intracerebral or oral route, with a short incubation period. The findings suggest the possibility of an unrecognised BES-like infection in cattle in the USA, with a clinical picture of sudden collapse without prior signs. [1994](J69.16.w1)
  • Initially TME was considered to have originated from scrapie, however oral inoculations of scrapie into mink have failed, while intracerebral inoculations have not always been successful, and epidemiological evidence indicated a link with use of "downer" or "non-ambulatory" cattle in feed for affected mink. TME isolated inoculated into cattle causes disease with lesions similar to those seen with experimental BSE and second passage of the Stetsonville strain through cattle did not influence incubation period or neurohistochemical changes. [1995](J42.113.w1)
  • The findings associated with the Stetsonville incident of TME have lead to the suggestion of an unrecognised TSE in cattle; "no such disease has been recognised in North American cattle."[1999] (B294.10.w10)
  • TME "appears to result from feeding mink either scrapie-infected sheep of cattle affected with an unidentified TSE." To date [2003] surveillance has not detected any cases of BSE in cattle in the USA. [J64.22.w6]


  • "It has become progressively clear that scrapie is a naturally occurring disease of goats and, though the majority of the reported cases were in direct contact with affected sheep, this was not so in all cases."(B298.10.w10)
  • It has been suggested that historically scrapie in sheep "was largely geographically confined to susceptible sheepflocks feeding off acidic volcanic soils in areas such as Iceland, the Aragon region of Spain and the Cheviot Hills/Anglesey in the UK". A vast array of factors pertaining to such landscapes were listed as being potential trigger factors for the initiation of scrapie, including "higher-than average levels of naturally occurring metal contaminants such as aluminium, manganese, and sulphur, as well as radioactive 'radon' contamination", also magnesium and selenium deficiency and the presence of poisonous alkaloidal plant populations such as ragwort. Several potential mechanisms for interference by these substances with PrP were postulated including "disturbance of crucial kinases involved in phosphorylation of membrane proteins like PrP, inhibition of cytochrome P450 detoxification enzyme activities, and exerting mutagenic effects" and, for the alkaloidal plants, inhibition of glycosylation of PrP. (J262.46.w2)
    • [However, no evidence was put forward to show that any of the substances do actually affect PrP. No reason was put forward why susceptible genotype sheep in other geographical areas with acidic volcanic soils should not have developed the disease. (V.w5)]
    • In Iceland, in the scrapie-endemic areas, there is no evidence of increased sporadic CJD occurring. (B292.w16)

Bovine Spongiform Encephalopathy (BSE):

  • In cattle in the UK an analysis of cases April 1985-March 1988 showed that cases occurred irrespective of whether or not any cattle had been brought into the herd or had contact with sheep. Similarly there was no association with treatments such as use of vaccines, hormones, organophosphorus fly sprays, synthetic pyrethroid sprays, ear tags and anthelmintics) given to calves young stock or adults. Weedkillers/herbicides had not been used on 22.9% of the initial 145 farms questioned and pesticides had not been used on 68.9% of the same 145 farms. From 501 cases with known parentage, 239 different sires were identified. For nine sets of female twins, cases were seen in only on of each pair, with the others remaining healthy in eight cases (the ninth had been culled one year earlier). It was noted that "there was no evidence of an association with any single compounder of proprietary feedstuffs, but all affected animals for which an accurate feeding history was available had received proprietary feedstuffs." Use of a computer simulation model indicated that adults and calves were exposed but risk of exposure for calves was 30 times that for adults, with exposure commencing in the winter of 1981/82 and continuing to at least the end of 1984, with an incubation period range 2.5 year to at least 8 years and a log normal distribution. (J3.123.w2)
  • Epidemiological data are consistent with an increased exposure of cattle to scrapie agent in feeds containing ruminant derived protein. Findings are consistent also with an increased exposure of cattle to a cattle-adapted strain which had been present in the cattle population for some time but with an infecting dose previously being insufficient to result in clinical disease during the normal lifetime of cattle. (J3.128.w2)
  • Several cases of spongiform encephalopathy in exotic bovidae in zoos or wildlife parks in the UK were noted to have occurred in the south of England, which was also where the risk of BSE had been greatest, and in animals which had, during their lives, been exposed to concentrate feed containing ruminant-derived protein (meat and bone meal). It was noted that the proportion of individuals affected (from small populations) was much greater than the proportion of the UK cattle population which was affected. (J3.130.w3)
  • UK: England 1989. One Tragelaphus strepsiceros - Greater kudu, nineteen months old. Probably maternal transmission. Never fed concentrates containing ruminant derived protein but dam had died with spongiform encephalopathy 15 months earlier. (J3.130.w3)
  • Probable transmission between individuals in three Tragelaphus strepsiceros - Greater kudu not thought to have had any contact with feed containing ruminant derived protein, but from a herd with previous cases of spongiform encephalopathy. (J3.132.w1)
  • Probable transmission between Tragelaphus strepsiceros - Greater kudu in a case when one female had been introduced into the London Zoo group (in which previous cases of spongiform encephalopathy had been see) and was not thought to have been exposed to feed containing ruminant-derived protein. (J3.134.w4)
  • Source of infection undetermined for one Oryx dammah - Scimitar oryx (Scimitar-horned oryx). This animal had been born in 1990, after the ban on ruminant-derived protein in ruminant feeds, and it was considered unlikely that she had been exposed to such material at either the collection of her birth or the collection she moved to. No cases had been recognised at the birth zoo nor in ruminants at the receiving zoo. The animal's dam remained live and well. (J3.135.w1)
  • A cheetah (Acinonyx jubatus - Cheetah (Felidae - Cats (Family))) which developed clinical signs in 1993 at Whipsnade Wild Animal Park was known to have been fed whole necks and cuts from sagitally split necks and lumbar regions of cattle which were considered unfit for human consumption. (J2.26.w2)
  • It is now [1999] considered probable that exotic ruminants born after the ban on the inclusion of ruminant derived protein in feed for ruminants may still have been exposed to ruminant derived protein due to contamination of feed (as is considered to have been the case with cattle in the UK. This would explain known cases in exotic ruminants. No cases have been reported in Tragelaphus strepsiceros - Greater kudu since 1992. (B209.17.w17)
  • Following experimental infection of mice with material from the brains of BSE-affected cattle and Tragelaphus angasii - Nyala and Tragelaphus strepsiceros - Greater kudu with spongiform encephalopathy, there were "no significant differences in the nature or distribution of vacuolation or ultrastructural findings". The results were considered to support the idea that cases of spongiform encephalopathy seen in small numbers of exotic ruminants within the Bovidae in the UK "are part of the same epidemic that currently affects cattle." (J224.84.w1)
  • Acinonyx jubatus - Cheetah (Felidae - Cats (Family)) "Duke". This animal's diet in the first 22 months of life had included parts of cattle and horses from a knacker's yard (not including heads), also occasionally stillborn calves. Additionally pigeons (self caught), rabbits and once a Soay sheep from the same collection. The diet from 1992 onwards was horsemeat and chickens. (J3.135.w1)
  • Tragelaphus strepsiceros - Greater kudu at Regent's park. Affected 5/8 animals born after February 1987. No diet including ruminant-derived protein was fed after February 1987 and three of the animals were born at three, nine and 25 months after the 1988 ban on the inclusion of ruminant derived protein in ruminant feeds in the UK. (J3.135.w1)
  • Macaca mulatta - Rhesus monkey (Cercopithecidae - Old-world monkeys (Family)) in France, 1991. Believed to be associated with exposure to food containing bovine material. (J98.348.w1)
  • On the basis of data available it is not possible either to confirm transmission between individuals in the Tragelaphus strepsiceros - Greater kudu and other antelope nor to rule out the possibility that all cases in zoo bovidae were due to continuing contamination of feed. (B23.101.w4, J3.135.w1)
    Cases of BSE have occurred in only a few of the species which are thought to have been exposed to the BSE agent. It is likely that there is variation between species in their susceptibility. Relatively high susceptibility may exist in Tragelaphus strepsiceros - Greater kudu, Acinonyx jubatus - Cheetah (Felidae - Cats (Family)) and Felis concolor - Puma (Felis - (Genus)), given the relatively large number of cases (in relation to the size of the population which may have been exposed) which have occurred in these species, although this variation in observed incidence between species may also be related to differences in incubation period between species and differences in intensity of exposure. (B23.101.w4, J3.135.w1)
  • "In at least a proportion of the prion diseases of humans, especially when there are abnormalities of the PrP gene, prion disease appears to arise spontaneously. it seems possible that such spontaneous cases may also arise in other species and there is currently no prospect of preventing this." (B23.101.w4)
  • Infection in lemurs and simians in France was presumed to be due to ingestion of feed contaminated with BSE agent as food supplements containing ingredients of cattle origin were known to be fed. (J135.96.w1)

Theories on the nature of the causative Agent of the TSE diseases

Protein only theory:

  • The infectious agent is a host protein, aberrantly processed through a post-translational event, and able to catalyse its own accumulation. The PrP protein is thought to be this protein.
  • It is suggested that the “species-barrier” is due to dissimilarities in amino acid sequence between the infectious agent and the cellular PrP of the new host.
  • The idea that the agent may not contain nucleic acid was suggested (J9.214.w2, J223.41.w1), and that it might be a self-replicating protein was put forward in 1967  (J9.215.w1) and refined by Prusiner (J22.216.w1)

Evidence for:

  • "PrPSc is the only known component of the infectious prion particles." (J135.95.w1)
  • Propagation of the agent responsible for prion diseases is thought to be mediated by PrPSc and to require a conformational change of normal cellular PrPC into PrPSc. (J248.2.w1)
  • "No virus particles are associated with infectivity.” (B297.1.w1)
  • No immune response to infection is found in an affected host.” (B297.1.w1)
    • Following experimental infection of mice with scrapie agent no evidence of a humeral antibody response could be detected using a variety of tests. (J216.111.w1)
  • No nucleic acid is associated specifically with infectivity.” (B297.1.w1)
    • No PrP-related nucleic acid was detected in purified infectious material (J255.40.w1)
  • Infectivity titre is associated with levels of an abnormal isoform of prion protein known as PrPSc.” (B297.1.w1)
  • There is no difference in primary amino acid structure between PrPC and PrPSc therefore no PrPSc-specific nucleic acid is required. (B297.1.w1)
  • Most of the variation in species specificity, incubation time and lesion profiles can be accounted for by variations in the PrP protein of the host and the degree of homology between host PrPC and donor PrPSc; this reduces the variation which needs to be attributed to “strain of agent” (B297.1.w1)
  • Familial TSEs occur in pedigrees with PrP gene mutations (B297.1.w1) and inherited TSEs are transmissible to experimental animals. (B302)
  • Transgenic mice carrying PrP gene mutations produced a TSE despite being kept in controlled conditions so that contamination with an exogenous agent can be avoided. (J22.250.w1) 
    • This disease was shown to be transmissible to mice carrying fewer copies of the transgene (J135.91.w1)
  • Using radiolabelled PrPC it has been shown that PrPSc was able to convert PrPC. into a protease resistant form of PrP in a cell-free system. However the conversion was extremely inefficient, requiring PrP “seed” in greater than 50-fold excess over the PrPC.; it was not therefore possible to detect any new infectivity in the converted PrP. (J9.370.w1)
  • Purification of prions from scrapie-infected hamster brain yielded proteins, apparent molecular size 27,000-30,000 daltons using sodium dodecyl sulfate polyacrylamide gels, which was relatively resistant to proteinase K under non-denaturing conditions, did not appear to be present in brains from uninfected hamsters, and appeared to correlate with the titre of the scrapie agent. (J22.218.w1)
  • Evidence for the protein-only hypothesis includes the fact that the main determinant of the species barrier of prion infections is the amino acid sequence of PrPC. (J248.2.w1)
  • The infectious agent has been shown to be resistant to a number of processes which are known to break down nucleic acids.
  • The infectious agent appears to co-purify with PrPSc.  (J22.218.w1)

Evidence against: 

  • Presence of different strains (D108, J9.391.w1).
    • It has been suggested that no mechanism has satisfactorily explained how PrP alone could specify and retain multifactorial TSE strain characteristics such as the ability of the BSE agent to retain its characteristics despite passage through many different species, determine incubation period in conjunction with host genotype) and specify targeting of lesions within the brain. (J9.391.w1)
    • Proponents of the protein-only theory suggest that the strains are controlled by PrP conformation. (D108)
  • There are >105 PrPres molecules present per infectious unit. (J22.279.w1)
  • Cell-free conversion of PrPC. to PrPSc has failed to prove a resultant increased infectivity. (D108, J22.279.w1)
  • Development of a neurodegenerative disease in mice overexpressing a mutant for of PrP is inconclusive evidence: no disease occurs if the mutant transgene is present only as a single-copy gene in the normal PrP locus, no abnormal protease-resistant PrP is detectable in the brains of the affected mice and transmission of the disease has not been possible to normal mice, only to transgenic mice expressing low levels of the mutant transgene. (J22.279.w1)
  • Fails to explain how the PrP of the infecting agent originally assumed the aberrant structure associated with infectivity, or how the different structures originated as a function of the different strains. (D132)
  • The different strains of agent. (D108)
  • It has been shown to be possible to transmit BSE to mice in the absence of detectable PrP-res. Development of disease in mice following inoculation of BSE material, and transmission of infection to further mice, occurred in the absence of detectable abnormal prion protein. (J22.275.w1)
    • "Because we could transmit a TSE without detectable cerebral PrPres accumulation in the case of interspecies transmission of the BSE agent, the hypothesized existence of an infectious agent in addition to PrPres becomes more likely; in view of the complexity of TSE strain properties, this agent may be a nucleic acid." (J22.275.w1)
    • "PrPres is clearly involved in the pathogenic process of TSEs. However it may not be the transmissible component of the infectious agent." (J22.275.w1)

Evidence for the involvement of another factor, generally referred to as “Protein X”

  • Experiments with transgenic mice found that Tg(HuPrP) mice, expressing high levels of human PrPC, were resistant to human prions, while transgenic TgMHu2M) mice, expressing chimeric PrP did show greater susceptibility. Crossing with PrnP0/0 mice (in which the mouse PrP gene has been ablated) increased the susceptibility of Tg(HuPrP)Prnp0/0 mice to human prions. The data were taken to imply that while the central domain of PrPC binds to PrPSc, there is also an interaction of a second domain of cellular PrP, probably near the C-terminus of PrP, with another macromolecule (provisionally named “protein X”, and that this was due to mouse MoPrPC binding to mouse (Mo) protein X more avidly that human HuPrPC to mouse protein X, thereby inhibiting the conversion of HuPrPC into PrPSc. It was assumed that this macromolecule was another protein, hence the name “Protein X”. (J255.83.w1)
  • Studies using scrapie-infected mouse neuroblastoma cells identified a discontinuous epitope to which the unidentified factor “Protein X” appeared to bind, in that alteration of various residues within this epitope prevented formation of PrPSc. PrPSc formation was prevented if a Human (Hu) residue was substituted at position 214 or 218, and was also prevented following substitution of a basic residue at positions 167, 171 or 218, all being within this epitope. (J135.94.w2)

Unconventional virus theory: 

  • This theory suggests that the agent of TSEs is a virus, if an unconventional one.

Evidence for: 

  • The agent of TSEs exists as several strains with distinct biological and pathological properties. (D108)
  • PrP-rich fractions which copurify with infectivity also contain small amounts of nucleic acid. (J22.279.w1)
  • Finding novel viruses can be difficult. (J22.279.w1)
  • Infectivity can be dissociated from PrP under certain conditions. (J22.275.w1, J135.92.w1, J227.6.w1)
  • Infectious samples contain nucleic acid. (J22.279.w1)
  • Familial occurrence of prion disease in humans is explainable as a genetic susceptibility to an infectious agent in the environment. (B297.1.w1)
  • Show some properties typical of viruses: filtration studies showed the agent to be of a size comparable with conventional viruses, being filterable to 100 nm in the case of kuru and CJD and 25 nm average pore diameter for scrapie and TME agent. (J22.197.w1, B297.1.w1, B302)
  • Replicate initially in the spleen and elsewhere in the reticuloendothelial system before replicating in the brain. (J22.197.w1, B297.1.w1, B302)
  • Specificity of host range (only affect certain species) (J22.197.w1, B297.1.w1, B302)
  • Adaptation to a new host involves shortening of the incubation period on serial passage. (J22.197.w1, B297.1.w1, B302)
  • Strains vary in virulence and pathogenicity. (J22.197.w1)
  • There is clonal selection of strains from wild stock by limiting dilution. (J22.197.w1)
  • Slow-growing strain interferes with replication of fast-growing strain in mice. (J22.197.w1)
  • Relative resistance to inactivation by UV light is considered to be similar to that of some other viruses, for example potato spindle tuber viroid, the smallest plant virus, with a naked single-stranded RNA of 120,000 daltons. (J22.197.w1)
  • Experimental data suggested a requirement for the presence of intact viral-like complexes for infectivity. (J135.92.w1)
  • Experiments have suggested that the majority of scrapie infection is inactivated by e.g. 0.535% hypochlorite and 0.01 M sodium metaperiodate, with only a resistant subpopulation of about 0.1-0.01% of the original agent being resistant. (B302 ref 103 –J9.308.w1.
    • Heat inactivation of scrapie agent rapidly inactivates the majority of the infectivity, with only a small subpopulation being resistant: 0.0005% of the original being highly resistant to 60°C inactivation when in the presence of brain homogenate. At 100°C 97% was destroyed within two minutes and when exposed to 121°C, 99.9999% of infectivity was destroyed during the one minute required to bring the sample to this temperature. (J22.223.w1)
    • The target size indicated by irradiation studies is compatible with that of a small virus. (J22.279.w1)

Evidence against:

  • A specific nucleic acid co-purifying with infectivity has not been found. (D108)
  • Virus particles not observed in infected tissue by electron microscopy; 
    • Some studies have reported the presence of particles, 10-12 nm diameter (smaller than any known virus) resembling viruses in scrapie-infected hamster brain (J98.343.w1, D132)
  • Scrapie agent was found to be very resistant to UV light, with almost no effect at a wavelength of 280 mu. (J9.214.w2)

Virino theory:

  • This theory suggests that the infectious agent is a small, noncoding, regulatory nucleic acid surrounded and protected by a host-coded protein. (D108, J9.391.w1) 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 (B293.w3, D108, D132)

Evidence for: 

  • Lack of immune response. (D108)
  • Presence of different strains. (D108)

Evidence against:

  • No nucleic acid component off the infective agent has been identified, possibly due to its small size or similarity to contaminating host nucleic acids (D108)
  • Lack of an immune response argues against the presence of nucleic acid in the agent. (D132)

Nemavirus theory:

  • This theory suggests that the TSE agent has a three-layer structure with an inner core of PrP/SAF, with ss-DNA coiled around this and an outer layer of protein surrounding this. (J135.85.w1). It is suggested that the ss-DNA codes for a protein which, by interacting with normal cellular PrP, results in conversion of PrPC to PrPSc. (J135.85.w1, J124.149.w1, B302)
  • The structure of the ssDNA is reported to be a "repeat uniform symmetrical multipalindromic repeat of (TACGTA)n. This would make the ssDNA base pair and coil, which would interfere with detection of the nucleic acid, explaining why many studies have failed to detect a nucleic acid. (J124.149.w1)

Evidence for:

  • Tubulofilamentous particles have been described in scrapie- and CJD- infected brain material. (J266.34.w1)
  • One researcher isolated single-stranded DNA strands of about 0.49 X 106 Daltons from nucleic acid preparations of scrapie-infected hamster brains but not from those of normal brains. (J265.216.w1)
  • Inoculation of ss-DNA derived from scrapie-infected animals, when combined with substances known to enhance uptake of DNA by cells, were found to transmit scrapie to hamsters. (J124.149.w1)
Evidence against:
  • Attempts by a different team of researchers to replicate the isolation of ssDNA described above (J265.216.w1) were not successful. (J223.77.w3)
  • The presence of TSE-specific tubulofilamentous particles has been challenged. (J274.55.w1)

Spiroplasma theory:

  • This theory suggests that the aetiological agents of the TSEs are spiroplasmas. Similar to mycoplasmas, spiroplasmas are prokaryotes, without a cell wall. (J93.25.w1, J271.60.w1)
  • A recent [2001] paper by the main proponent suggested that "we propose that a Spiroplasma sp. is associated and may be the proximate cause of TSE" then noted that "at this juncture, we don't know whether a Spiroplasma sp. triggers conversion of PrP to PrPres, or whether Spiroplasma infection is a consequence of TSE." (J271.60.w1)

Evidence for:

  • Electron microscopy of a brain biopsy of an individual with CJD revealed coiled membranous structures 850-1,000 nm long and 75-137.5 nm width, within axons, mainly in presynaptic terminals. They were considered to closely resemble Spiroplasma. (J273.103.w1)
  • Intracellullar membranous spiral inclusions, 375-660nm long and 50-88nm wide were described in the processes of cortical cells of patients with CJD and considered to morphologically resemble spiroplasma organisms. (J271.40.w1)
  • Following passage of a CJD strain in hamsters, spiroplasma-like inclusions were seen in neurons (J226.35.w1)
  • Strain GT-48 spiroplasma when inoculated into newborn rodents, caused a fatal encephalitis with a spongiform pathology considered to resemble that of humans with CJD. (J45.114.w1)
  • Morphological similarity between the fibrillar cytoarchitecture of Spiroplasma mirum and scrapie-associated fibrils. (J93.25.w1)
  • Antiserum to SAF reacted with protease-resistant fibril proteins purified from Spiroplasma mirum. (J93.25.w1)
  • PCR amplification identified Spiroplasma 16S rDNA in TSE-infected brain tissues from 13/13 CDJ cases and 5/9 scrapie cases but 0/50 control brains. "PCR, using primers specific for the Spiroplasma sp. ribosomal RNA gene, consistently produces a 276-bp PCR product in all CJD cases tested." (J271.60.w1)

Evidence against:

  • Absence of detection by serology or culture. (J272.109.w1)

Alternative external environment hypotheses put forward for the development of BSE:

  • Autoimmune theory
    • This theory suggests that BSE is an autoimmune disorder brought about by exposure of cattle to common environmental bacteria, with molecular similarities between bacterial proteins and brain proteins. (J268.105.w1)
      • It has been reported that animals with BSE have elevated levels of immunoglobulin A autoantibodies to brain components (neurofilaments and myelin) and to the soil saphrophyte Acinetobacter calcoaceticus , which has " sequences cross-reacting with bovine neurofilaments and myelin." (J267.67.w1)
      • Mice with an intact immune system but without PrP do not develop disease following inoculation of TSE agents. (D116)
      • Mice which are immunodeficient still develop disease if inoculated intracerebrally with TSE agents. (D116)
      • This theory cannot explain the sudden emergence of BSE in thousands of animals, nor why it has occurred predominantly in the UK. (D116)
  • Organophosphate hypothesis. 
    • An alternative hypothesis for the aetiology of BSE has been put forward, suggesting that BSE is caused by in utero exposure to high-dose lipophilic formulations of organophosphates (OPs) applied to cattle for the prevention and eradication of warble fly in the UK and to exposure to OPs from used sheep-dip sprayed onto fields and in food ingredients where OPs may be used to protect against insect infestations during storage. (J262.46.w2). It was suggested that in the UK there was a "sudden 'switch on' of a fatal combination of variable, idiosyncratic biochemical factors that were specifically relevant to the UK environment." (J262.46.w2)
      • It was stated that "wherever clusters of TSE incidence have surfaced, such as on the MAFF farm in Exmoor, on captive mink and deer farms in North America, in the various zoo species, in the UK cat population, etc., a source of in utero exposure to lipophilic formulations of OP pesticides (or OP residual metabolites found in their OP treated feedstuffs) that could potentially covalently modify or mutate the PrP genetic/translation/folding pathways can be identified." (J262.46.w2). However no references or evidence to support this statement were put forward.
      • It was suggested that changes in warble fly treatment policy in 1982 (from once to twice yearly) and an increase in the use of high-dose phosmet from 1985 onward were responsible for the epidemic. (J262.46.w2)
        • This theory "cannot be reconciled with the epidemiology and is not supported by research." (B301)
        • This is not consistent with recent analysis, using GIS and other data (B302)
        • This is not consistent with the epidemiological evidence. (D116)
        • It has been suggested that the OPs (particularly Phosmet) had their effect on "those genetically susceptible Holstein cattle bewitched by BSE" (N10.X.w1) however there is no evidence of any genetic susceptibility to BSE in cattle. (J3.135.w2).
    • A multiplicity of hypotheses were put forward for how and at what stage of PrP formation the OP might affect the PrP of the fetus. (J262.46.w1)
      • However no evidence was presented that any of these events has occurred or even that the putative OPs are capable of such effects on PrP. (J262.46.w1)
      • Experimentally, although phosmet, the OP suggested to be responsible for BSE, has been shown to increase expression of PrP on the cell surface of neuroblasmoma cells in vitro  it has not been shown to convert PrPC to PrPSc. It is not possible to rule out the possibility that certain organophosphates might increase susceptibility to TSEs. (B302)
    • No explanation was given for the transmissibility of TSE diseases. (J64.22.w1)
    • An in vitro study found that neither the phthalimido organophosphorus ectoparasiticide Phosmet, nor its metabolites, resulted in a conformational change of recombinant mouse cellular prion protein from an alpha helix to a beta pleated sheet form. The researchers considered that this data indicates that Phosmet is "very unlikely to have initiated the BSE epidemic by a simple direct mechanism of conformational change in the prion protein." (J287.26.w1)
  • Manganese excess/copper deficiency hypothesis
    • This theory suggests that BSE and other TSEs are linked to environments providing excessive levels of manganese and inadequate intakes of copper, selenium, iron and zinc. (J262.54.w1).
      • It has been shown that the spatial distribution in England of low copper/high manganese in topsoils do not coincide with the incidence distribution of cases of BSE. (D116)
    • Further elaborations of this theory combine the hypothetical excess of manganese and importance of a trivalent form of the manganese ion with (a) ultraviolet photooxidation of manganese-loaded prion protein in the retina (J262.57.w1) and/or (b) "infrasonic shock" due to tectonic disturbances, supersonic aeroplanes etc.; a diagram appears to suggest that ozone and ultrasound pregnancy diagnosis may also play a role in this hypothetical mechanism for "assault of Mn loaded/Cu depleted circadian-auditory-vestibular pathways of the bovine". (J262.60.w1)

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Authors & Referees

Authors Dr Debra Bourne MA VetMB PhD MRCVS (V.w5)
Referee Suzanne I Boardman BVMS MRCVS (V.w6)

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