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From: TSS ()
Conversion of the BASE Prion Strain into the BSE Strain: The Origin of BSE? 1 Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milan, Italy, 2 Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, Torino, Italy, 3 Istituto Zooprofilattico Sperimentale della Lombardia ed Emilia Romagna, Brescia, Italy, 4 Friedrich-Loeffler-Institut, Institute for Novel and Emerging Infectious Diseases, Greifswald, Insel Riems, Germany, 5 Department of Neurological and Visual Science, Section of Clinical Neurology, Policlinico G. B. Rossi, Verona, Italy Atypical neuropathological and molecular phenotypes of bovine spongiform encephalopathy (BSE) have recently been identified in different countries. One of these phenotypes, named bovine “amyloidotic” spongiform encephalopathy (BASE), differs from classical BSE for the occurrence of a distinct type of the disease-associated prion protein (PrP), termed PrPSc, and the presence of PrP amyloid plaques. Here, we show that the agents responsible for BSE and BASE possess different biological properties upon transmission to transgenic mice expressing bovine PrP and inbred lines of nontransgenic mice. Strikingly, serial passages of the BASE strain to nontransgenic mice induced a neuropathological and molecular disease phenotype indistinguishable from that of BSE-infected mice. The existence of more than one agent associated with prion disease in cattle and the ability of the BASE strain to convert into the BSE strain may have important implications with respect to the origin of BSE and spongiform encephalopathies in other species, including humans. full text ; http://pathogens.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.ppat.0030031 Greetings, how might the above study relate to the below studies ??? ...tss Personal Communication Subject: re-BSE prions propagate as either variant CJD-like or sporadic CJD Date: Thu, 28 Nov 2002 10:23:43 -0000 From: "Asante, Emmanuel A" To: "'flounder@wt.net'" Dear Terry, I have been asked by Professor Collinge to respond to your request. I am a Senior Scientist in the MRC Prion Unit and the lead Thank you for your interest in the paper. In respect of your first question, the simple answer is, yes. As you will find in the paper, we have managed to associate the alternate phenotype to type 2 PrPSc, the commonest sporadic CJD. It is too early to be able to claim any further sub-classification in respect of Heidenhain variant CJD or Vicky Rimmer's version. It will take further studies, which are on-going, to establish if there are sub-types to our initial finding which we are now reporting. The main point of the paper is that, as well as leading to the expected new variant CJD phenotype, BSE transmission to the 129-methionine genotype can lead to an alternate phenotype which is indistinguishable from type 2 PrPSc. Best wishes. Emmanuel Asante <> ____________________________________ Dr. Emmanuel A Asante MRC Prion Unit & Neurogenetics College School of Medicine (St. Mary's) Norfolk Place, Tel: +44 (0)20 7594 3794 Fax: +44 (0)20 7706 3272 email: e.asante@ic.ac.uk (until 9/12/02) New e-mail: e.asante@prion.ucl.ac.uk (active from now) ____________________________________ Copyright © 2002 European Molecular Biology Organization MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College, Queen Square, London WC1N 3BG, UK 1Corresponding author e-mail: j.collinge@prion.ucl.ac.uk Received August 1, 2002; Revised September 24, 2002; Accepted October 17, 2002. Abstract Variant Creutzfeldt–Jakob disease (vCJD) has been recognized to date only in individuals homozygous for methionine at PRNP codon 129. Here we show that transgenic mice expressing human PrP methionine 129, inoculated with either bovine spongiform encephalopathy (BSE) or variant CJD prions, may develop the neuropathological and molecular phenotype of vCJD, consistent with these diseases being caused by the same prion strain. Surprisingly, however, BSE transmission to these transgenic mice, in addition to producing a vCJD-like phenotype, can also result in a distinct molecular phenotype that is indistinguishable from that of sporadic CJD with PrPSc type 2. These data suggest that more than one BSE-derived prion strain might infect humans; it is therefore possible that some patients with a phenotype consistent with sporadic CJD may have a disease arising from BSE exposure. snip...FULL TEXT ; http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12456643 Originally published in Science Express on 11 November 2004 Variant Creutzfeldt-Jakob disease (vCJD) is a unique and highly distinctive clinicopathological and molecular phenotype of human prion disease associated with infection with bovine spongiform encephalopathy (BSE)–like prions. Here, we found that generation of this phenotype in transgenic mice required expression of human prion protein (PrP) with methionine 129. Expression of human PrP with valine 129 resulted in a distinct phenotype and, remarkably, persistence of a barrier to transmission of BSE-derived prions on subpassage. Polymorphic residue 129 of human PrP dictated propagation of distinct prion strains after BSE prion infection. Thus, primary and secondary human infection with BSE-derived prions may result in sporadic CJD-like or novel phenotypes in addition to vCJD, depending on the genotype of the prion source and the recipient. Medical Research Council (MRC) Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK. snip... Although caution must be exercised in extrapolating from animal models, even where, as here, faithful recapitulation of molecular and pathological phenotypes is possible, our findings argue that primary human BSE prion infection, as well as secondary infection with vCJD prions by iatrogenic routes, may not be restricted to a single disease phenotype. These data, together with the recent recognition of probable iatrogenic transmission of vCJD prions to recipients of blood (21, 22), including a PRNP codon 129 Met/Val heterozygous individual (22), reiterate the need to stratify all human prion disease patients by PrPSc type. This surveillance will facilitate rapid recognition of novel PrPSc types and of any change in relative frequencies of particular PrPSc subtypes in relation to either BSE exposure patterns or iatrogenic sources of vCJD prions. http://www.sciencemag.org/cgi/content/abstract/306/5702/1793 J Neuropsychiatry Clin Neurosci 17:489-495, November 2005 This study characterizes the type and timing of Historically, psychiatric manifestations have been Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease ratio of protease-resistant prion protein (PrPSc), and type 2 PrPSc display unglycosylated core fragments of acids 82 and 97, respectively. Methods We generated anti-PrP monoclonal antibodies to K cleavage sites. These antibodies, which were Findings We studied 114 brain samples from 70 patients Every patient classified as CJD type 2, and all variant cerebellum and other PrPSc-rich brain areas, with a Interpretation The regular coexistence of multiple electrophoretic PrPSc mobilities as surrogates for classifications. into debate and introduce interesting questions about human CJD types. For example, do human prion types exist in a dynamic equilibrium in the brains of affected individuals? Do they coexist in most or even all CJD cases? Is the biochemically identified PrPSc type simply the dominant type, and not the only PrPSc species? 64. A member noted that at the recent Neuroprion meeting, a study was Other work presented suggested that BSE and bovine amyloidotic spongiform http://www.seac.gov.uk/minutes/95.pdf Models Qingzhong Kong, Ph.D., Assistant Professor, Pathology, Case Western Reserve Bovine Amyloid Spongiform Encephalopathy (BASE) is an atypical BSE strain ***These results indicate that BASE is transmissible to humans and suggest that BASE is more virulent than There is a growing number of human CJD cases, and they were presented last He estimates that it may be up to 14 or 15 persons which display selectively snip... >> Differences in tissue distribution could require new regulations >> regarding specific risk material (SRM) removal. snip...end full text 33 PAGES ; http://www.bseinquiry.gov.uk/files/mb/m11b/tab01.pdf http://www.bseinquiry.gov.uk/files/yb/1988/10/00001001.pdf It was, however, performed in the USA in 1979, when it was shown that cattle inoculated with the scrapie agent endemic in the flock of Suffolk sheep at the United States Department of Agriculture in Mission, Texas, developed a TSE quite unlike BSE. 32 The findings of the initial transmission, though not of the clinical or neurohistological examination, were communicated in October 1988 to Dr Watson, Director of the CVL, following a visit by Dr Wrathall, one of the project leaders in the Pathology Department of the CVL, to the United States Department of Agriculture. 33 The results were not published at this point, since the attempted transmission to mice from the experimental cow brain had been inconclusive. The results of the clinical and histological differences between scrapie-affected sheep and cattle were published in 1995. Similar studies in which cattle were inoculated intracerebrally with scrapie inocula derived from a number of scrapie-affected sheep of different breeds and from different States, were carried out at the US National Animal Disease Centre. 34 The results, published in 1994, showed that this source of scrapie agent, though pathogenic for cattle, did not produce the same clinical signs of brain lesions characteristic of BSE. http://www.bseinquiry.gov.uk/ 1: J Infect Dis. 1994 Apr;169(4):814-20. Intracerebral transmission of scrapie to cattle. Cutlip RC, Miller JM, Race RE, Jenny AL, Katz JB, Lehmkuhl HD, DeBey BM, Robinson MM. USDA, Agriculture Research Service, National Animal Disease Center, Ames, IA 50010. To determine if sheep scrapie agent(s) in the United States would induce a disease in cattle resembling bovine spongiform encephalopathy, 18 newborn calves were inoculated intracerebrally with a pooled suspension of brain from 9 sheep with scrapie. Half of the calves were euthanatized 1 year after inoculation. All calves kept longer than 1 year became severely lethargic and demonstrated clinical signs of motor neuron dysfunction that were manifest as progressive stiffness, posterior paresis, general weakness, and permanent recumbency. The incubation period was 14-18 months, and the clinical course was 1-5 months. The brain from each calf was examined for lesions and for protease-resistant prion protein. Lesions were subtle, but a disease-specific isoform of the prion protein was present in the brain of all calves. Neither signs nor lesions were characteristic of those for bovine spongiform encephalopathy. MeSH Terms: Animals Brain/microbiology* Brain/pathology Cattle Cattle Diseases/etiology* Cattle Diseases/pathology Encephalopathy, Bovine Spongiform/etiology* Encephalopathy, Bovine Spongiform/pathology Immunoblotting/veterinary Immunohistochemistry Male Motor Neurons/physiology Prions/analysis Scrapie/pathology Scrapie/transmission* Sheep Sleep Stages Time Factors Substances: Prions http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8133096&dopt=Citation 9/13/2005 Page 16 of 17 Intracerebral transmission of scrapie to cattle FULL TEXT PDF; SNIP... Discussion WE conclude that American sources of sheep scrapie are transmissible to cattle by direct intracerebral inoculation but the disease induced is NOT identical to BSE as seen in the United Kingdom. While there were similarities in clinical signs between this experimental disease and BSE, there was no evidence of aggressiveness, hyperexcitability, hyperesthesia (tactile or auditory), or hyperemetria of limbs as has been reported for BSE (9). Neither were there extensive neurologic lesions, which are primary for BSE, such as severe vacuolation of neurons and neuropil or neuronal necrosis and gliosis. Although some vacuolation of neuropil, chromotolysis in neurons, and gliosis were seen in the brains of some affected calves, these were industinguishable from those of controls. Vacuolated neurons in the red nucleus of both challenged and normal calves were considered normal for the bovines as previously described (50). PrP-res was found in ALL CHALLENGED CALVES REGARDLESS OF CLINCIAL SIGNS, and the amount of PrP-res positively related to the length of the incubation. ... snip... WE also conclude from these studies that scrapie in cattle MIGHT NOT BE RECOGNIZED BY ROUTINE HISTOPATHOLOGICAL EXAMINATION OF THE BRAIN AND SUGGEST THAT DETECTION OF PrP-res by immunohistochemistry or immunoblotting is necessary to make a definitive diagnosis. THUS, undiagnosed scrapie infection could contribute to the ''DOWNER-COW'' syndrome and could be responsible for some outbreaks of transmissible mink encephalopathy proposed by Burger and Hartsough (8) and Marsh and harsough (52). ... snip... Multiple sources of sheep affected with scrapie and two breeds of cattle from several sources were used inthe current study in an effort to avoid a single strain of either agent or host. Preliminary results from mouse inoculations indicate multiple strains of the agent were present in the pooled inoculum (unpublished data). ... Transmission of the sheep scrapie to cattle was attempted in 1979 by using intracerebral, intramuscular, subcutaneous, and oral routes of inoculation of 5, 8- to 11-month old cattlw with a homologous mixture of brain from 1 affected sheep (61, 62). ONE of the 5 cattle develped neurologic signs 48 months after inoculation. Signs were disorientation, incoordination, a stiff-legged stilted gait, progressive difficulty in rising, and finally in terminal recumbency. The clinical course was 2.5 months. TWO of the 5 cattle similarly inoculated with brain tissue from a goat with scrapie exhibited similar signs 27 and 36 months after incoluation. Clinical courses were 43 an 44 days. Brain lesions of mild gliosis and vacuolation and mouse inoculation data were insufficient to confirm a diagnosis of scrapie. This work remained controversial until recent examination of the brains detected PrP-res in all 3 cattle with neurologic disease but in none of the unaffected cattle (62). Results of these studies are similar to ours and underscore the necessity of methods other than histopathology to diagnose scrapie infection in cattle. We believe that immunologic techniques for detecting PrP-res currently provide the most sensitive and reliable way to make a definitive diagnosis... http://www.bseinquiry.gov.uk/files/sc/seac17/tab03.pdf Visit to USA ... info on BSE and Scrapie http://www.bseinquiry.gov.uk/files/yb/1988/10/00001001.pdf http://www.ngpc.state.ne.us/cgi-bin/ultimatebb.cgi?ubb=get_topic;f=12;t=000385 12/10/76 AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE Office Note CHAIRMAN: PROFESSOR PETER WILDY snip... A The Present Position with respect to Scrapie A] The Problem Scrapie is a natural disease of sheep and goats. It is a slow and inexorably progressive degenerative disorder of the nervous system and it ia fatal. It is enzootic in the United Kingdom but not in all countries. The field problem has been reviewed by a MAFF working group (ARC 35/77). It is difficult to assess the incidence in Britain for a variety of reasons but the disease causes serious financial loss; it is estimated that it cost Swaledale breeders alone $l.7 M during the five years 1971-1975. A further inestimable loss arises from the closure of certain export markets, in particular those of the United States, to British sheep. 9/13/2005 Page 17 of 17 It is clear that scrapie in sheep is important commercially and for that reason alone effective measures to control it should be devised as quickly as possible. Recently the question has again been brought up as to whether scrapie is transmissible to man. This has followed reports that the disease has been transmitted to primates. One particularly lurid speculation (Gajdusek 1977) conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of mink are varieties of a single "virus". The U.S. Department of Agriculture concluded that it could "no longer justify or permit scrapie-blood line and scrapie-exposed sheep and goats to be processed for human or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise the human dementias" Whether true or not. the hypothesis that these agents might be transmissible to man raises two considerations. First, the safety of laboratory personnel requires prompt attention. Second, action such as the "scorched meat" policy of USDA makes the solution of the acrapie problem urgent if the sheep industry is not to suffer grievously. snip... 76/10.12/4.6 http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf THE infamous USA SPORADIC CJDs, something to ponder; IF the USA TSE in cattle all does not look like UK BSE, why would all USA human TSE look like UK nvCJD??? over 20 strains of scrapie documented to date with new atypical strains now being documented in sheep and goat i.e. BSE. atypical strains of BSE/TSE showing up in cattle in different countries? ALL animals for human/animal consumption must be tested for TSE. ALL human TSEs must be made reportable Nationally and Internationally, OF ALL AGES... IN a time when FSIS/APHIS/USDA/FDA et al should be strengthening the TSE regulations, it seems corporate interest has won out again over sound science and consumer protection from an agent that is 100% fatal for the ones that go clinical. With the many different atypical TSEs showing up in different parts of the world, and with GWs BSE MRR policy (the legal policy of trading all strains of TSEs), the battle that has waged for the last 25 years to eradicate this agent from this planet will be set back decades, if not lost for good. ... Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518 9/13/2005 kind regards, terry FULL TEXT ; http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-2.pdf tss
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