Transmissible Encephalopathies in Animals

Richard H. Kimberlin

ABSTRACT their physicochemical stability and vacuolar degeneration of grey matter their apparent failure to stimulate any areas of the brain and spinal cord in sheep and goats is the kind of protective host response to (hence the generic term, "spongiform best known of the transmissible . The biochemical nature of encephalopathies"). In addition brain encephalopathies of animals. The these agents is still a matter of extracts contain large numbers of combination of maternal transmission controversy but many workers con- characteristic amyloid fibrils seen by of infection and long incubation sider them to be outside the known negative stain electron microscopy (4). periods effectively maintains the range of and viroids. For this These fibrils are known as scrapie- infection in flocks. A single sheep reason the term "unconventional associated fibrils (SAF: sometimes (Sip) controls both experimental and viruses" is often used. The terms called " rods") but they are an natural scrapie and the discovery of "virinos" and "" have entered important diagnostic feature of the allelic markers could enable the use of the literature as synonyms for the related diseases as well (5). sire selection in the control of the scrapie family of agents but this may Scrapie-associated fibrils are easily natural disease. Studies of experimen- be premature. Such terms are best purified from clinically affected brain tal rodent scrapie show that neuroin- used to identify the specific hypo- (6). They consist mainly of a mem- vasion occurs by spread of infection thetical concepts about the nature of brane glycoprotein (7) PrP, whose from visceral lymphoreticular tissues these agents that prompted their messenger RNA is present in many along nerve fibers to mid-thoracic introduction. types of cell (8) but is found in cord. The slowness of scrapie is due to The most radical concept, embo- relatively high concentrations in restrictions on replication and cell-to- died in the much published "prion" normal neurons (9). In the course of cell spread of infection affecting hypothesis (1), is that the scrapie agent infection, this is modified neuroinvasion and subsequent neuro- is an infectious protein which some- posttranslationally (8,10), accumu- pathogenesis. Probably both stages in how directs its own replication. The lates in brain (11) and acquires the mice are controlled by Sinc gene, the "virino" hypothesis (2,3) draws upon ability to form SAF. Sometimes, murine equivalent of Sip. The glyco- the large body of evidence for the modified PrP is deposited extracellu- protein PrP may be the normal existence of a scrapie-specific , larly to form large cerebral amyloid product ofSinc gene. Posttranslation- which is likely to be nucleic acid. It plaques visible by light microscopy ally modified PrP forms the disease suggests that the putative scrapie (12,13). In appearance, these plaques specific "scrapie associated fibrils" nucleic acid is very small, not resemble the amyloid plaques asso- and may also be a constituent of the translated and therefore dependent on ciated with Alzheimer's disease (AD) infectious agent. Scrapie-like diseases a host-coded protein to form an but the latter are formed from a have been reported in mink and infectious agent. Taxonomically, protein that is quite different from several species of ruminants including "virinos" would fit in between viruses modified PrP (14). There are other cattle. All of them may be caused by and viroids. fundamental differences in the patho- the recycling of scrapie infected sheep Several naturally occurring diseases logy of AD and the spongiform material in animal feed. The human are caused by members of the scrapie encephalopathies and it is emphasized health implications are discussed. family of agents. Typically these that AD is not known to be diseases are associated with very long transmissible. incubation periods (often several Scrapie in sheep and goats is the INTRODUCTION years). Overt clinical signs have a best understood member of the chronic progressive course over weeks transmissible spongiform encephalo- The title of this paper refers to or months and invariably culminate in pathies (15). Two related diseases of scrapie and a group of related diseases death. Pathological lesions occur only humans are and Creutzfeldt- of the central nervous system (CNS). in the central nervous system (CNS). Jakob disease (CJD) but neither These diseases are caused by a class of The characteristic lesion seen by light appears to be epidemiologically infectious agents which are notable for microscopy is a noninflammatory, related to scrapie (16). This is not true

Institute for Animal Health, AFRC & MRC Neuropathogenesis Unit, West Mains Road, Edinburgh, EH9 3JF, United Kingdom. Present address: SARDAS, 27 Laverockdale Park, Edinburgh, EH13 OQE, United Kingdom. Submitted June 5, 1989.

30 Can J Vet Res 1990; 54: 30-37 of transmissible mink encephalopathy endemic infection of cattle as scrapie is evidence of scrapie replication in the (TME), a rare disease of ranch-reared of sheep. At the moment there is no CNS. This pattern is consistent with mink which occurs when animals are evidence one way or the other but if it infection via the alimentary tract. The sufficiently exposed orally or by did occur, endemic BSE would be as early and persistent infection of scarification to scrapie infected feed difficult to control as scrapie. extraneural tissues may play a role in (17). Transmissible mink encephalo- The occurrence of BSE has reem- initiating neuroinvasion (especially pathy can be experimentally transmit- phasized the importance of scrapie with less neuroinvasive scrapie strains: ted from mink to mink (for example research from both fundamental and see 34). In addition the lymphoreticu- by injection of infected tissue) but practical points of view. Considerable lar system (LRS) is likely to be there is no evidence that this occurs progress has been achieved in many important epidemiologically in pro- naturally. In other words, mink are areas of scrapie research. What viding a reservoir from which infec- "dead-end" hosts for exogenously follows is a brief, selected synthesis of tion can be spread maternally and acquired scrapie infection (18). recent findings which reveal some- horizontally. An infected ewe can Transmissible mink encephalo- thing of the way these diseases work. transmit scrapie to several successive pathy provides an important prece- Two recent books give a more lamb crops before she develops the dent which is relevant to the appear- comprehensive account of current disease (15). This is an efficient way by ance of scrapie-like diseases in five knowledge of the subject (26,27). which scrapie infection is maintained species of captive ruminants in the last in a flock. In contrast, studies of ten years. These are chronic wasting NATURAL SCRAPIE experimental TME in mink indicate disease (CWD) of mule deer (19) and There are no conceptual difficulties very low levels of infectivity in the Rocky Mountain elk (20) in the USA, with the epidemiology of scrapie LRS which could be a major reason single cases of spongiform encephalo- infection in sheep and goats. Infection why there is no natural spread of pathy in nyala and gemsbok in the UK is most commonly transmitted from infection from mink to mink (18). (21), and a large scale epidemic of ewe to lamb, both up to time of Although scrapie is caused by an bovine spongiform encephalopathy parturition and afterwards when ewe infectious agent, host genetic factors (BSE) in the UK (22,23). and lamb run together (15). The age- have a considerable influence on the Of these diseases, BSE is the most incidence curve (with a peak in the development of disease in sheep (but, important. It has the pathological fourth year) reflects the incubation interestingly, not in goats). Selective hallmarks of the whole group (vacuo- period of maternally transmitted breeding studies have been carried out lation, and SAF formed from modi- infection. There is also horizontal with Cheviot (35), Herdwick (36) and fied PrP; 22,24). Transmissibility to spread of infection between unrelated Swaledale (37) sheep injected with mice has recently been demonstrated adults and this can account for some either Cheviot or Swaledale sources of (25). Epidemiological evidence of the scrapie cases in old sheep (28). scrapie. Together these studies suggest strongly suggests that BSE is caused However the mechanisms of maternal that all sheep carry a gene, Sip, which by scrapie infection getting into the and horizontal spread of infection are controls scrapie incubation period cattle population via meat and bone not fully understood. Transplancental (38). This gene has two alleles, sA and meal supplements to concentrated infection and infection via milk are pA. Most sheep carrying the sA allele feed stuffs (23). Differences in the level two possibilities. The placenta from an will develop experimental scrapie (i.e. of concentrate feeding can account for infected ewe is a good source for the sA is dominant for susceptibility) but the 30-fold lower incidence of BSE in spread of infection to unrelated incubation periods are usually longer beef suckler herds compared to dairy animals (29) and the high physico- in the heterozygotes than in the herds. If, like mink, cattle are "dead- chemical stability of the scrapie agent homozygotes (34). Sheep homozygous end" hosts for scrapie infection, then (30) is a major factor in the buildup of for pA are far less susceptible. They the ban (introduced in the UK in mid- contamination on farm premises. rarely develop the disease after 1988) on the feeding of animal derived There is no direct evidence that semen subcutaneous injection of scrapie but protein to ruminants should lead to or ova can become infected and there they can be susceptible to intracere- the disappearance of BSE. However, is much interest in the possibility that bral injection, after extremely long the long incubation period, estimated embryo transfer may provide a basis incubation periods. This means that to be from 2.5 to 8 years (23), means for importing sheep genetic material the response of individual Sip geno- that no reduction in incidence can be with a reduced risk of importing types depends on the route of injection expected until 1992 at the earliest. The scrapie (31). and probably the effective dose of current incidence of BSE is about 1 in Sheep can be experimentally scrapie (34). There is evidence that Sip 1000 of adult dairy cattle so a very infected by oral dosing (e.g. with fetal gene also controls natural scrapie (39) large number of cases (tens of membranes; 29) or by scarification but studies of Suffolk (40) and Ile-de- thousands) will have occurred by the (32) and these are likely to be natural France (41) sheep suggest a recessive early 1990's (23). routes of infection. Pathogenesis pattern in which the most susceptible A more worrying scenario is that studies of natural scrapie show that genotype is Sip sAsA. infection, having got into the cattle the earliest sites of infection include The susceptibility of the sApA population, may be able to spread tonsil, ileum and proximal colon as heterozygotes to experimental disease from cow to calf or cow to cow. In well as spleen and lymph nodes from a contrasts with their relative insuscepti- other words BSE may become an variety of sites (33). Only later is there bility to the natural disease. In theory,

31 this difference could be used to reduce is rapidly established in spleen, lymph ganglion cells (52). Experiments the incidence of natural scrapie by nodes and some other tissues of the involving intraocular infection and using Sip pApA sires to eliminate the LRS (47). removal of the eye at various times Sip sAsA genotype (34). Such a Neuroinvasion is the key stage in the afterwards gave an estimate for the strategy would depend on the reasona- pathogenesis of disease. With all the rate of intra-axonal spread of scrapie. ble but unproven assumption that nonneural parenteral routes, the first This value was also about 1 mm/day most wild-type strains of scrapie site of replication in the CNS is in the (53). interact with the alleles of Sip gene in thoracic spinal cord. The main The neuronal targeting of infectivity the same way. There is also the neuroinvasive site is located in the provides a simple basis for under- question of which stages of scrapie region between thoracic vertebrae 4 standing the neuropathogenesis of pathogenesis are controlled by Sip. At and 9. This and other findings strongly scrapie. For example, the duration of the moment this question remains suggest that infection spreads along the replication phase in brain (from unanswered. However, there is good visceral sympathetic fibers which enter first detection to the onset of clinical evidence that Sinc gene in mice is the this region of the spinal cord as part of disease) varies considerably with the homologue of Sip in sheep (38). The the splanchnic nerve complex (see 47). route of infection: intraocular major action of Sinc gene is on scrapie Direct proof that infection can spread > intracerebral injection of anterior multiplication in the nervous system, from the peripheral nervous system to brain > intraspinal infection (thoracic not the LRS(42). If Sip works in the the CNS was obtained by injecting cord) and all the nonneural peripheral same way, it could control neuroinva- scrapie into the sciatic nerve (49). routes (47). These differences have two sion and subsequent events in the Serial splenectomy studies showed implications. First, much of the nervous system on which the develop- that spleen plays a major role in infectivity and consequential brain ment of clinical disease depends. This neuroinvasion but it is only needed for damage is irrelevant to the pathogene- means that even though Sip sApA a few weeks to initiate the process (50). sis of disease which depends on sheep may not develop the disease they However spleen is not the only tissue infectivity reaching and replicating in could be persistent carriers of infec- from which neuroinvasion can take a limited number of "clinical target tion in the LRS and contribute to the place. In splenectomized mice, infec- areas" (CTA). Secondly, the spread of spread of infection within flocks (34). tion spreads to the thoracic spinal cord scrapie infection in neural tissue is It is difficult to study this possibility from other visceral sites of scrapie restricted and the site of entry (or of without either a laboratory test for replication, almost certainly lymph injection) in the CNS determines the scrapie infection or convenient nodes (50). Splenectomy has no effect pathways by which infection can reach markers for the alleles of Sip gene. on pathogenesis after intragastric the CTA (47,54). Infectivity entering Recently, restriction fragment length infection. In this case, early scrapie the brain from spinal cord (after i.p., polymorphisms have been found replication takes place in Peyer's s.c or i.v. injection) is targeted more which can identify the alleles of Sinc patches and the evidence favors spread directly to the CTA than i.c. injected gene in mice (43-45). Another study of infection to the thoracic spinal cord scrapie when more complex pathways has sought similar allelic markers for via the enteric and sympathetic are involved, presumably involving Sip gene with encouraging results (46). nervous systems (5 1). The same several neuron-to-neuron steps. Reliable markers could be invaluable pathway probably applies to natural Scrapie replication in the CTA then to further studies of scrapie epidemiol- scrapie because, as mentioned earlier, drives the production of lesions which ogy and the development of new those parts of the intestines which leads to the clinical disease. strategies for disease control. contain Peyer's patches are among the The nature of the primary lesions is earliest tissues in which infection can not known. An attractive hypothesis is PATHOGENESIS OF be detected (33). that modification of normal PrP, and EXPERIMENTAL SCRAPIE Once scrapie replication is estab- other presumably essential , Studies of short incubation models lished in the thoracic spinal cord, causes progressive dysfunction (and of scrapie (60-250 days) have revealed infection spreads slowly to the rest of maybe death) in certain populations of much about the pathogenesis of the the cord, enters the brain via the neurons. Major unanswered questions disease after infection by nonneural, medulla and eventually reaches concern the normal function of PrP peripheral routes such as subcutan- anterior regions of the brain (47). and the nature ofthe posttranslational eous (s.c.), intraperitoneal (i.p.) and There is also centrifugal spread of modifications that are caused by intravenous (i.v) (47). Infection is infection to other parts of the scrapie which result in the formation rapidly and widely distributed from peripheral nervous system. Two of SAF and extracellular amyloid the site of injection via the blood estimates put the rate of spread of cores (55). supply. The 1000-fold range in the infection within the CNS at about efficiency of infection by different 1 mm/day (47). Good evidence that CONTROL OF SCRAPIE routes (i.v. > i.p. > s.c.) appears to be scrapie can spread within neurons PATHOGENESIS related to the extent of this immediate comes from studies of intraocular One of the great paradoxes of and short-lived viremic phase (48). infection; the earliest appearance of scrapie and the related diseases is why There is no evidence that blood-borne infectivity in brain is in the contralat- they are so slow when no known host infection can directly establish scrapie eral superior colliculus which is the responses are induced to slow them replication in the CNS but replication major projection area of retinal down. Recent studies have revealed

32 two mechanisms underlying the long less accessible cells in the nonclinical at the neural stage of pathogenesis incubation periods of scrapie. Both target areas remained. High plateau (and may control neuroinvasion as mechanisms are related to restrictions titers would then mask the continuing well). It has already been suggested on scrapie replication within cells and spread of infection and replication in that Sip gene may control natural on the spread of infection between the clinical target areas which must be scrapie in the same way. cells. among the last permissive cells to be There seems to be a universal reached. The same principles apply to AND occurrence of plateau concentrations the cell-to-cell spread of scrapie IN SCRAPIE of scrapie infectivity in the LRS (47). infection in the LRS, as described There is biological evidence that Plateaux develop well in advance of below. each allele of Sinc gene codes for a clinical disease and persist for the Comparisons of a range of short product (presumably protein) which remaining life-span of the host. and long incubation models in rodents forms a multimeric structure involved Plateau titers comparable to those in show that, with all of them, scrapie in the overall process of scrapie the LRS also occur in the peripheral replication in the LRS begins quite replication (62,63). The evidence nervous system but always at a soon after infection (47). The major stems from the restrictions on scrapie concentration at least tenfold lower differences occur at the two subse- replication and spread of infection than the maximum titers found in the quent stages of pathogenesis. described above, and the variety of CNS. With one major exception, The first is exemplified by the 87V allelic interactions by which many infectivity plateaux occur in the spinal strain of scrapie injected i.p. into Sinc scrapie strains are recognized (38,63). cord and brain. The exception is the p7p7 mice. Depending on the dose However the nature of the protein(s) 263K strain of scrapie in hamsters, the injected, either a proportion of mice coded by the alleles of Sinc gene has fastest of all scrapie models, in which develop scrapie after long and remained unknown until recently, disease develops before replication in extremely variable incubation periods when two major discoveries were brain becomes limited. (450-700 days; 60) or neuroinvasion made. There is evidence that scrapie fails to occur and there is no clinical First, restriction fragment length replication takes place in stable, long- disease at all (61). The restriction on polymorphisms (RFLP) associated lived cell populations: radiation neuroinvasion presumably acts at the with PrP gene were found which resistant cells in the LRS (56,57) and cellular interface between the LRS correlated with the s7 and p7 alleles of neurons. Plateau titers can therefore and the peripheral nervous system. It Sinc (also called Prn-i gene; 43,45). be seen in terms of a finite number of can be bypassed by injecting 87V Crossbreeding studies established a intracellular "sites" for the infectious scrapie intracerebrally when all the close linkage between the PrP and scrapie agent in a finite number of mice develop the disease after highly Sinc genes. A similar linkage of PrP nonreplaceable cells. The concept of uniform incubation periods. The and Sip genes in sheep is implied by site limitation is strongly supported by limited neuroinvasiveness of 87V the discovery of RFLP's which competition experiments in which the scrapie provides an obvious model for correlate with the Sip alleles sA and prior injection of a "slow" scrapie the existence of infected carriers in pA (46). Secondly, PrP gene sequence strain can completely prevent a sheep scrapie (see earlier). studies revealed two amino differences second, much "faster" scrapie strain Most other scrapie models give between PrP of Sinc s7s7 mice and from producing the disease. Competi- highly uniform incubation periods Sinc p7p7 mice (44). This second tion can occur with either the after i.p. infection. A comparative finding suggests that the PrP and Sinc intracerebral or the i.p. route of study of five of them (including two genes may be one and the same; in injection confirming site limitation in very slow models) showed no restric- other words that PrP is the Sinc gene both LRS and CNS (58,59). tion on neuroinvasion which was product. If this is true, the high level of In addition to the limitations on the initiated within a few weeks of PrP expression in normal neurons (9) number of scrapie permissive cells, infection (42). The differences in and the control of scrapie neuropatho- there are also restrictions on the cell- incubation period were due to differ- genesis in mice by Sinc gene (42) invite to-cell spread of infection. In the CNS, ences in the overall rates of replication speculation that PrP may form sites this is shown by the differences in the and spread of infection, from neuroin- involved in (a) the spread of infection duration of the replication phase in vasive sites in the peripheral nervous to neurons and from one neuron to brain according to the site of entry or system to the clinical target areas in another, or (b) with scrapie replication of injection of scrapie (see above). In the CNS. These five scrapie models within neurons. terms of the neuronal targeting of differed in either the strain of agent or These developments emphasize the infectivity, the basis of this restriction the Sinc genotype of the mice. increasing importance of PrP in could be differences in the physiologi- Therefore both factors interact to scrapie pathogenesis; PrP is likely to cal and neurochemical properties of control scrapie neuropathogenesis be the product of Sinc gene and connecting neurons which would (42). modified PrP forms the disease create a hierarchy of scrapie permis- In conclusion, the pathogenesis of specific fibrils, SAF. In addition there sive cells according to their accessibil- scrapie is controlled at two stages; is a substantial copurification of ity (47,54). The gradual slowing down neuroinvasion and the subsequent scrapie infectivity with purified SAF of replication in brain, as the plateau is replication and spread of infection in from scrapie brain (6,11,64), and other approached, would occur as fewer and nervous tissue. Sine gene in mice acts evidence links modified PrP with

33 infectivity (65). This association IMPLICATIONS ARISING FROM rated into meat and bone meal suggests that modified PrP may be THE NEW SCRAPIE-LIKE DISEASES supplements and some infectivity either the infectious protein of the At the time of writing, over 3500 apparently survives the rendering "prion" hypothesis or else the protec- cases of BSE have occurred in the UK. process. For many years now, material tive host-coded protein required by This enormous epidemic has stimu- from scrapie cases and from preclini- the "virino" hypothesis. lated a reassessment of some features cally infected sheep may have posed a The idea that PrP may be involved of the scrapie family of diseases. threat to livestock fed on concentrates. with both the etiological agent of First, it is interesting that the five The recycling of contaminated sheep scrapie and with the host genetic most recent diseases have all appeared protein could have contributed to the control of incubation period is causing in domesticated or captive ruminants. occurrence of natural scrapie: there confusion in some minds. It is impor- Indeed, with the exceptions of humans would be no species barrier to impede tant to recognize the fundamental and mink, ruminants are the hosts for transmission to sheep and such difference between a disease of genetic all the occurrences would be hard to detect origin and known spongiform encephalo- the genetic control of an pathies. There are 172 species of four- against a background of endemic infectious disease. There is overwhelm- chambered scrapie. Contamination of concen- ing evidence that scrapie is ruminants and 169 ofthese caused by an are in either the Cervidae (41 species) trated feedstuffs may also have been infectious agent which exhibits the the unsuspected cause of TME in the properties of strain or Bovidae (128 species) families. So variation and far, a scrapie-like disease has appeared USA in outbreaks where mink had not mutation (38,66,67). This means that in members of five out of the nine been fed untreated sheep carcasses or the scrapie agent has a genome which corresponding subfamilies (Cervinae, offal (70). A similar explanation has contains scrapie-specific information. been mentioned for the isolated The fact that, in Odocoileinae, Bovinae, Hippotragi- sheep and mice, a nae and Caprinae). It rather looks as occurrences of CWD in mule deer and single host gene and the scrapie genome Rocky Mountain elk. The fact that have an though rumination may be associated interdependent action in with a certain proclivity to infection by BSE has only been reported in the UK controlling incubation period must not scrapie-like agents. offers limited reassurance to other obscure the independent existence of The second point is that the countries in which a threat may exist these two factors. comparatively high efficiencies of due to endemic scrapie or the importa- On the "virino" hypothesis the infection by the parenteral routes used tion of contaminated meat and bone scrapie genome is probably a small, in studies of scrapie pathogenesis (47) meal. nontranslated nucleic acid. The idea may have overshadowed the impor- At the same time the scale of the that Sinc (and probably Sip) gene may tance of the oral/alimentary route in outbreak of BSE in the UK means that provide the precursor of the protein natural infection (51). The latter (along additional factors must have increased that protects the scrapie nucleic acid with scarification) is clearly involved the exposure to scrapie infection, but offers a very simple basis for the in natural scrapie, especially in the with regional variations to account for control of incubation period by a host horizontal spread of infection (29,33) the greater incidence of BSE in the gene product interacting with the Oral infection, combined with scarifi- southern part of the country. scrapie genome (2). It is therefore cation, is strongly implicated in the Moreover, computer modelling of the important to find this putative nucleic transmission of human kuru during outbreak suggests a relatively sudden acid genome. endocannibalism of dead relatives increase in exposure which started in On the "prion" hypothesis, modi- (68,69) and also in the transmission of 1981/82 (23). Possible factors include fied PrP becomes the genome of the scrapie to mink to give TME (17). In a greater inclusion of sheep heads for agent. Somehow, it must direct the the latter case, scarification probably rendering and changes in the render- posttranslational modification of comes into play when there is fighting ing process; for example, the use of normal, noninfectious, PrP to pro- between littermates at feeding time. lower temperatures and the greatly duce more of the modified, infectious Finally, the transmission of scrapie to reduced use of organic solvents to form. If, in addition, PrP is the Sinc cattle (to give BSE) is clearly asso- extract fats. Theoretically, another gene product, then the effect of the ciated with the ingestion of contami- possibility is the sudden emergence of alleles of Sinc gene will be determined nated feed (23). Nothing is known of a mutant scrapie strain which just by the host-coded amino acid the origin of CWD in mule deer and happened to be more pathogenic for sequence of normal PrP. Subse- Rocky Mountain elk (19,20), or of the cattle. However the form of the quently, normal PrP must be modified spongiform encephalopathies in a epidemic would require the simultane- posttranslationally, in as many specifi- nyala and a gemsbok (21); but the ous emergence of this mutant strain in cally different ways as there are scrapie advent of BSE makes a scrapie source many flocks (or cattle herds) through- strains (at least ten) capable of ofinfection by the oral route seem very out the country: this does not seem replicating in a given host genotype. likely. likely (23). These are the stringent conditions for A third point arising from BSE is In the wake of BSE, it now seems the replication of a proteinaceous that exposure to scrapie infection is possible that all the scrapie-like genome. It is difficult to see how they not just by the feeding of untreated diseases in animals originate from might be met until the differences sheep carcasses or offal, as was endemic scrapie infection in sheep and between normal and modified PrP are originally supposed with TME (17). goats. If the level of infection is high known (1 1,55). Infected sheep material is incorpo- enough, the direct feeding of sheep

34 tissue or rendered products can enable However the risk cannot be regarded 4. MERZ PA, SOMERVILLE RA, WIS- infection to cross the species barrier as nonexistent, for two reasons. First, NIEWSKI HM, IQBAL K. Abnormal and cause disease in other hosts, the widespread use of bovine products fibrils from scrapie-infected brain. Acta Neuropathol (Berl) 1981; 54: 63-74. especially ruminants. Therefore, the in food, vaccines, medicines and 5. MERZ PA, ROHWER RG, KASCSAK R, recycling of animal proteins in surgical devices may add significantly WISNIEWSKI HM, SOMERVILLE RA, feedstuffs should either be curtailed or to the total human exposure. The GIBBS CJ Jr, GAJDUSEK DC. Infection- the conditions ofrendering changed to second reason has to do with crossing specific particle from the unconventional take account of the high physicochem- the species barrier when at least two slow diseases. Science 1984; 225: 437- 440. ical stability of scrapie agent and processes can occur (67,74). One of 6. DIRINGER H, GELDERBLOM H, HIL- inactivate it (71). these, the "donor species effect", MERT H, OZEL M, EDELBLUTH C, What can be said about the scrapie- involves unknown modifications to KIMBERLIN RH. Scrapie infectivity, like diseases of humans? Because of the pathogenesis which can reduce the fibrils and low molecular weight protein. precedent set by TME, the possibility efficiency of infection at the first Nature 1983; 306: 476-478. 7. STAHL N, BORCHELT DR, HSIAO K, that CJD is caused by exposure to passage in the new host. The other PRUSINER SB. Scrapie prion protein scrapie has been intensively studied involves strain selection from preexist- contains a phosphatidylinositol glycolipid. ever since the transmissibility of CJD ing mixtures or of mutants derived from Cell 1987; 51: 229-240. was demonstrated in 1968 (72). A large single scrapie strains. Indeed, experi- 8. OESCH B, WESTAWAY D, WALCHLI number of investigations have failed to mental passage from one species to M, McKINLEY MP, KENT SBH, show link between another (e.g. from mice to hamsters) is AEBERSOLD R, BARRY RA, TEMPST any epidemiological P, TEPLOW DB, HOOD LE, PRUSINER scrapie and CJD (16). Sheep and goats an effective way of isolating mutant SB, WEISSMANN C. A cellular gene are not a major reservoir of CJD strains. It is therefore possible that the encodes scrapie PrP 23-30 protein. Cell infection and no other animal reservoir transmission of scrapie from sheep to 1985; 40: 735-746. has been identified. In the author's cattle may alter the population of scra- 9. KRETZSCHMAR HA, PRUSINER SB, opinion, CJD could be a relatively pie strains to which humans are ex- STOWRING LE, DE ARMOND SJ. posed. If the strains selected by cattle Scrapie prion proteins are synthesized in common, nonpathogenic infection of neurons. Am J Pathol 1986; 122: 1-5. man which only rarely causes clinical have a greater pathogenicity for humans 10. BASLER K, OESCH B, SCOTT M, disease (see 73). This hypothesis means than sheep strains, the risks to humans WESTAWAY D, WALCHLI M, GROTH that the epidemiology of the disease is would be increased accordingly. DF, McKINLEY MP, PRUSINER SB, not an accurate reflection of the From a practical standpoint, it is WEISSMANN C. Scrapie and cellular PrP virtually impossible to quantify these isoforms are encoded by the same chromo- epidemiology ofthe infection. Unfortu- somal gene. Cell 1986; 46: 417-428. nately, the hypothesis cannot be tested risks. Strain typing is a protracted 11. BOLTON DC, BENDHEIM PE, MAR- until there is an efficient (nonbiologi- exercise (38,66,67) and even if a MORSTEIN AD, POTEMPSKA A. cal) test for the infectious agent. selection of scrapie strains in cattle was Isolation and structural studies of the intact Kuru is a case. It have demonstrated, there is no way of scrapie agent protein. Arch Biochem special may evaluating directly their increased or Biophys 1987; 258: 579-590. originated from a case of CJD (68), but decreased for humans. 12. DE ARMOND SJ, McKINLEY MP, the practice of ritual cannibalism of pathogenicity BARRY RA, BRAUNFELD MB, dead relatives selectively passaged Neither are there diagnostic tests of McCOLLOCH JR, PRUSINER SB. infection (other than bioassay) to Identification of prion amyloid filaments in neuropathogenic strains within the measure the level of human exposure. scrapie-infected brain. Cell 1985; 41: 221- population (73). Because there was no And the long incubation periods of 235. maternal transmission of this infection, these diseases mean that it could be at 13. McBRIDE PA, BRUCE ME, FRASER H. the cessation of cannibalism has least a decade before an actual risk Immunostaining of scrapie cerebral amy- resulted in the gradual disappearance of loid plaques with antisera raised to scrapie- revealed itself by an increased incidence associated fibrils (SAF). Neuropathol Appl kuru (69). (It will be remembered that of CJD. Because of these difficulties Neurobiol 1988; 14: 325-336. there is no maternal transmission of there is no alternative but to assume 14. ROBERTS GW, LOFTHOUSE R, infection in mink and the hope is that that BSE poses a real risk, however ALLSOP D, LANDON M, KIDD M, the same will apply to cattle.) In PRUSINER SB, CROW TJ. CNS amyloid small, and take precautionary steps to proteins in neurodegenerative diseases. conclusion, it may be that only two of reduce it to an absolute minimum. Neurology (NY) 1988; 38: 1534-1540. the scrapie-like diseases are maintained 15. DICKINSON AG. 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