NR ANZT

AU Almond,J.W.

TI Will bovine spongiform encephalopathy transmit to humans?

QU British Medical Journal 1995 Nov 25; 311(7017): 1415-6

IA http://bmj.bmjjournals.com/cgi/content/full/311/7017/1415/a

PT Article

VT The possibility that bovine spongiform encephalopathy might transmit to humans has been acknowledged since the disease was first recognised in British cattle. Indeed, one of the control measures introduced in 1989 - that of removing certain offals from bovine carcasses - was designed to minimise the risk of transmission to humans. The proscribed offals were those which were known to contain high levels of infectivity in sheep infected with scrapie and in mouse models of transmissible spongiform encephalopathies, there being (at that time) no information about the tissue distribution and levels of infectivity of bovine spongiform encephalopathy in bovine tissues at the various stages of the disease. Reassurance was provided by the observation that transmissible spongiform encephalopathies from other animals showed no evidence of transmission to humans. This is in spite of the fact that, for sheep scrapie at least, there is widespread exposure to, and consumption of, infected animals. Nevertheless, transmissible spongiform encephalopathies can transmit from one species to another, and for any given donor species there is no way of predicting which recipient species will be susceptible.
How can the risk to humans be assessed in light of current knowledge? One question is whether bovine spongiform encephalopathy has a greater (or different) potential for cross species transmission than scrapie and other non-human transmissible spongiform encephalopathies. This is relevant irrespective of whether one accepts the proposition that bovine spongiform encephalopathy is derived from sheep scrapie, since passage through cattle may confer new transmission properties. Observations in experimental animals suggest that transmission of a transmissible spongiform encephalopathy to one foreign host can result in an infection that can then transmit to a second, initially insusceptible, foreign host.[i] Actually, a similar experiment may have been done serendipitously by exposing cats. Feline spongiform encephalopathy appeared in the 1980s, apparently as a new disease.[ii] The feline spongiform encephalopathy agent was examined by strain typing and found to have the same strain phenotype as bovine spongiform-encephalopathy.[iii] Assuming that cats have been equally exposed to sheep scrapie and to bovine spongiform encephalopathy, the observations suggest that bovine spongiform encephalopathy has a different, and possibly broader, host range than circulating scrapie strains. We do not yet know whether this apparently novel host range of bovine spongiform encephalopathy extends to humans.
What molecular factors influence cross species transmission? These remain incompletely defined, but the seminal experiments by Scott et al established that the genotype of the prion (PrP) gene is the major factor.[iv] Indeed, the species barrier to transmission between mouse and hamster was overcome by transferring the hamster PrP gene into a mouse by genetic engineering. Although recent reports have suggested the involvement of additional factors,[v,vi] homophilic interactions between PrP in the inoculum and PrP in the host seem necessary for transmission to occur,[vii] with amino acids 96-167 possibly being most important.[vi-viii] What inferences can be drawn by comparing the PrP sequences of humans and cattle? It would be comforting if the degree of homology between them was lower, or at least no greater, than that between humans and sheep. Unfortunately this is not the case. Overall, the bovine sequence is closer (albeit slightly) to the human sequence than is the sheep sequence, and the 96-167 region has only five differences rather than six. Reassuringly, however, a second important region of the molecule, the C-terminal,[vi] is equally diverged.[ix]
What conclusions can be drawn about the present cases of Creutzfeldt-Jakob disease? Obviously, any change in the pattern of presentation of Creutzfeldt-Jakob disease in Britain compared with countries free of bovine spongiform encephalopathy would be cause for concern. However, the incidence of Creutzfeldt-Jakob disease in Britain has shown no significant increase in recent years and is similar to that elsewhere. The cases in farmers do suggest a significantly elevated risk for this group versus the general population. However, an elevated risk is also observed for farmers in other countries where there is a zero or very low incidence of bovine spongiform encephalopathy.[x] The risk is therefore unlikely to be related to bovine spongiform encephalopathy. The cases in teenagers are possibly of greater concern since such cases are generally extremely rare. However, it is possible that in earlier times, when there was less awareness of the disease, cases in teenagers were misdiagnosed. We need to be sure that the present cases are more than simply coincidental before we conclude that they represent a real change in the presentation of Creutzfeldt-Jakob disease.
Where do we go from here? We need definitive experiments to establish whether bovine spongiform encephalopathy can transmit to humans and whether it has transmitted to humans. Experimental procedures that might provide answers are available. Collinge and others have recently published evidence that mice transgenic for the human PrP gene can be used as a model for human PrP related diseases." [xi,xii]Similar mice, on a mouse PrP' background (lacking their own PrP gene) are available[xiii] and should be tested for susceptibility to bovine spongiform encephalopathy by various routes. A positive outcome, particularly if the mice were relatively resistant to sheep scrapie, would be evidence that bovine spongiform encephalopathy can transmit to humans. Bruce et al have described "strain phenotypes" based on lesion profile and transmission characteristics for various isolates of scrapie and bovine spongiform encephalopathy.[iii] The bovine spongiform encephalopathy phenotype is distinct and, moreover, stable even on passage through another species such as cat or antelope. If the present cases of Creutzfeldt-Jakob disease have been caused by bovine spongiform encephalopathy it is likely that this will show up in strain typing tests. As a matter of urgency, therefore, necropsy material from all of the present cases should be strain typed. Any presence of the bovine spongiform encephalopathy phenotype should be regarded as strong evidence that bovine spongiform encephalopathy has transmitted to humans.
i. DeArmond SJ. Overview of the transmissible spongiform encephalopathies prion protein disorders. Br Med Bull 1993;49:725-37.
ii. Wyatt JM, Pearson GR, Smerdon TN, Gruffydd Jones TJ, Wells GA, Wilesmith JW. Naturally occurring scrapie-like spongiform encephalopathy in five domestic cats. Vet Rec 1991;129:233-6.
iii. Bruce M, Chree A, McConnell I, Foster J, Pearson G, Fraser H. Transmission of bovine spongiform encephalopathy and scrapie to mice - strain variation and the species barrier. Philosophical Transactions of the Royal Society of London series B - Biological Sciences 1994-343:405-11.
iv. Scott M, Foster D, Mirenda C, Serban D, CoufaI F, Walchli M,et al. Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques. Cell 1989;59:847-57.
v. Telling GC, Scott M, Mastrianni L, Gabizon R, Torchia M, Cohen FE, et al. Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell 1995;83:79-90.
vi. Telling GC, Scott M, Mastrianni L, Gabizon R, Torchia M, Cohen FE, et al. Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell 1995;85:79-90.
vii. Scott M, Groth D, Foster D, Torchia M, Yang SL, De Armond SJ, et al Propagation of prions with artificial properties in transgenic mice expressing chimeric PrP genes. Cell 1993;73:979-88
viii. Schatzl HM, Dacosta M, Taylor L, Cohen FE, Prusiner SB. Prion protein gene variation among primates. J Mol Biol 1995;245:362-74.
ix. Goldmann W, Hunter N, Martin T, Dawson M, Hope J. Different forms of the bovine PrP gene have five or six copies of a short, G-C-rich element within the protein-Coding exon. J Gen Virol 1991;72:201-4.
x. Will RG. Creutzfeldt-Jakob disease surveillance in the United Kingdom. CJD Surveillance Unit Annual Report 1995;4(abstract)
xi. CoIlinge J, Palmer MS, Sidle KCL, Gowland I, Medori R, Ironside J, et al Transmission of fatal familial insomnia to laboratory-animals. Lancet 1995; 346 569-70.
xii. Telling GC, Scott M, Hsiao KR, Foster D, Yang SL, Torchia M, et al. Transmission of Creutzfeldt-Jakob disease from humans to transgenic mice expressing chimeric human-mouse prion protein. Proc Natl Acad Sci USA 1994-91:9936-40.
xiii. Whittington MA, Sidle KCL, Gowland I, Meads J, Hill AF, Palmer MS, et al Rescue of neurophysiological phenotype seen in PrP null mice by transgene encoding human prion protein. Nature Genetics 1995;9: 197-201

ZR 13 Zitate

AD School of Animal and Microbial Sciences University of Reading Reading RG6 2AH Jeffrey W Almond professor
Laboratory of Central Nervous Studies National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda

SP englisch

PO England

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OR Prion-Krankheiten 1

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