ATYPICAL BSE I.E. BASE H AND L TYPE UPDATE USA DECEMBER 2007
***PLEASE NOTE***
Subject: SEAC New forms of Bovine Spongiform Encephalopathy 1 August 2007Date: August 5, 2007 at 10:41 am PST
SEAC
Position Statement
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New forms of Bovine Spongiform Encephalopathy
Issue
1. SEAC considered the implications of scientific research on recentlyidentified novel forms of bovine spongiform encephalopathy (BSE).
Background
2. Very low numbers of cattle with abnormal prion proteins (PrPsc) withdifferent biochemical properties from those normally associated with BSEhave been detected in active surveillance programmes in a number ofcountries. SEAC considered (SEAC 97, May 2007) published and unpublishedresearch relating to these putatively new forms of BSE.
Characterisation of cases
3. Different forms of BSE were initially identified and distinguished fromclassical BSE on the basis of their PrPsc profiles in biochemical tests. AllBSE cases identified to date conform to one of three different PrPscprofiles on western blot tests. The European Union (EU) Community ReferenceLaboratory has suggested that cases be classified on the basis of theseprofiles as classical, L- or H-type BSE. The key distinguishing features inwestern blot tests are the lower concentration of the diglycosylated bandand the slightly lower molecular mass of unglycosylated band of PrPsc inL-type BSE, and the higher molecular mass of the unglycosylated band inH-type BSE, compared with classical BSE. A western blot method todiscriminate between the three types of BSE has been developed .
4. All the reported cases of L-4,5,6,7 and H-type7,9,8,9 BSE have beendetected during active surveillance of healthy slaughtered animals or fallenstock. In the majority of cases, retrospective investigations indicated thatthese animals either showed no clinical signs of BSE or showed non-specificsigns such as ataxia and recumbency. As these cases have been detectedfollowing active rather than passive surveillance, it has not been possibleto observe the clinical signs associated with L- or H-type BSE in sufficientdetail to assess whether there are differences in the clinical featuresbetween L-type, H-type and classical BSE. However, a significant distinctionbetween classical BSE and L- and H-type BSEs is the age distribution ofcases as L- and H-type BSE are found in older cattle with an age range of5.5 to 19 years. One putative L-type BSE case was aged two years6, howeverthe BSE typing of this case has not been verified. Around 85% of L- orH-type BSE cases have been found in animals more than 10 years old, which ismuch older than most cases of classical BSE.
5. Neuropathological investigations suggest that PrPsc may be more widelydistributed, with a different brain distribution pattern for L- and H-typeBSE, compared with classical BSE. However, these investigations are limitedby the very low number of animals for which a complete brain has beenavailable for analysis. There are no data on the peripheral distribution ofPrPsc or infectivity of L- and H-type BSE or on the pathogenesis of thesediseases. However, studies to assess the tissue distribution of infectivityand PrPsc in animals throughout the incubation period followingintracerebral challenge are underway.
Prevalence
6. As there is no regulatory requirement to specify the type of BSE whennotifying the EU or the World Organisation of Animal Health of BSE cases, itis not possible to accurately quantify the number of H- or L-type BSE casesthat have occurred world-wide. Information presented to SEAC indicated thatat least 37 cases of L- and H-type BSE have been identified world-wide todate. These cases are widely distributed geographically with L-type casesidentified in a number of European countries and Japan, and H-type casesidentified in a number of European countries and North America.
7. Due to the different approaches to surveillance between countries,proportions of animals tested and methods used, which do not necessarilyinclude systematic molecular typing, these surveillance systems are notequally capable of detecting L- and H-type BSE. Furthermore, surveillanceprocedures, including the most appropriate brain region to sample, have notbeen optimised for the detection of L- and H-type BSE. Therefore, it is notpossible to accurately assess and compare the prevalence of L- and H-typeBSE in different countries. Origins and Causes
8. It is not known whether L- or H-type BSE are newly emerging forms of BSEor whether they have existed for some time and have only come to lightfollowing extensive active surveillance programmes in the EU and elsewhere,together with the introduction and development of new biochemical tests.Studies using historic frozen brain samples from cattle collected frompassive surveillance during the early years of the UK BSE epidemic areunderway to investigate whether L- and H-type BSE existed in the UK in thepast. However, if the prevalence of these BSE types was low, these studiesmay not identify many, if any, cases.
9. Genetic analyses of a few L- and H-type BSE cases4,5,8,9 have notidentified associations between the occurrence of such cases and knowngenetic polymorphisms in the prion protein gene. There are no mutations inthe prion protein gene open reading frame in all, but one, sequenced case.However, the analyses conducted to date are limited by the small number ofcases and controls analysed. Thus, a genetic cause of the disease cannot beruled out.
10. No detailed epidemiological investigations have been conducted toinvestigate the possible causes for, or links between, L- and H-type BSEcases. No geographical clusters of L- and H-type BSE cases have been foundto date. Therefore, it is not possible to rule out feed related,environmental or spontaneous causes for these types of cases.
Transmission studies
11. Transmission studies5,10,11 have demonstrated that both L- and H-typeBSE are transmissible to other species by the intracerebral route. Nostudies have assessed the transmissibility by the oral route. Thus, theavailable information shows that it is possible for species other thancattle to develop these diseases upon infection. However, these data do notallow an assessment of the susceptibility to infection from the most likelynatural route of exposure.
12. L-type BSE has been transmitted to wild-type, bovinised, ovinised andhumanised mice as well as to cattle and a cynomolgus macaque byintracerebral inoculation. Incubation periods, clinical signs,neuropathology as well as the neurological distribution of PrPsc weredistinct from classical BSE13,12. With the exception of transmissions towild-type mice, primary transmissions resulted in clinical disease. Althoughprimary transmission to wild-type mice did not result in clinical disease,secondary transmissions from some of these animals resulted in clinicaldisease. Sub-passage of L-type BSE in wild-type12 and ovinised mice13suggests that L-type BSE may be converted to an infection of a similarphenotype to classical BSE. However, further experiments using serialsub-passages of infections in a range of species are required to more fullyinvestigate whether L-type BSE may convert to a disease with a classical BSEphenotype.
13. H-type BSE has been transmitted to wild type, bovinised and ovinisedmice by intracerebral inoculation with incubation periods, neuropathologyand neurological distribution of PrPsc distinct from classical and L-typeBSE.
14. Studies of intracerebral transmission of H-type BSE to cattle andcynomolgus macaques . To date, clinical disease has developed from oneintracerebral inoculation of H-type BSE to cattle. Oral transmissions of L-and H-type to cynomolgus macaques are underway.
Human and animals health implications15. There are too few data to enable an assessment of the naturaltransmissibility of L- and H-type BSE between cattle, or to sheep or goats.The present feed control measures which prevent feeding of mammalian meatand bone meal to ruminants would limit the spread of these forms of BSE tocattle, sheep and goats should they be transmissible to these species by theoral route.
16. Similarly, the lack of data on the oral transmissibility of L- or H-typeBSE to humanised mice or non-human primates does not allow an assessment ofthe human health implications of ingestion of meat from animals infectedwith L- or H-type BSE. The differing clinical features of L-type andclassical BSE in the cynomolgus macaque suggest that if L-type BSE were everto be transmitted to humans, its clinical presentation may differ from thatof vCJD. It is possible, therefore, that, if transmitted to humans, it couldbe identified by continuing surveillance of unusual neurological conditionsin place in the UK.
Conclusions
17. L- and H-type BSE have not yet been fully characterised, however datafrom biochemical, neuropathological and transmission studies suggest that L-and H-type and classical BSE may be distinct strains of prion disease. Incontrast to classical BSE, L- and H-type BSE infections are mostly detectedin animals of older age with most of the infected animals identified to dateover 10 years of age. Although L- and H-type BSE may be diseases thatpredominantly affect older cattle, it is possible that infections may occurat a young age and develop over a long period of time. The origins andpossible routes of transmission, if transmissible under natural conditions,of L- and H-type BSE are not known. Due to the older age of the casesidentified, wide geographical distribution and their apparent low number, itis possible they may have arisen spontaneously, however feed borne orenvironmental transmission cannot be ruled out.
18. As data on the oral transmissibility of L- and H-type BSE are lacking,it is not possible to fully assess the animal and human health implications.However, as the occurrence of L- and H-type BSE appears to be low, and dueto the feed control measures in place, the risk of spread to other cattle,sheep and goats is likely to be very low assuming that, as with classicalBSE, environmental transmission is negligible. For these reasons, andbecause of the BSE control measures in place to protect the food supply,assuming that the specific risk material controls are similarly effectivefor L- and H-type and classical BSE, the risk to human health is likely tobe very low to negligible. However, given the paucity of data on L- andH-type BSE, a close watching brief should be maintained on the findings ofresearch in this area.
SEAC July 2007
References
1SEAC 97 discussion papers available at
http://www.seac.gov.uk/agenda/agen100507.htm
2Published and unpublished data from the Institute for Novel and EmergingInfectious Diseases, Germany presented by Dr M. Groschup, the InstitutoNazionale Neurologico, Italy presented by Dr F. Tagliavini, the Unite AgentsTransmissibles Non Conventionnels, France presented by Dr T. Baron, theIstituto Zooprofilattico Sperimentale del Piemonte, Italy presented by Dr P.Acutis, the National Animal Disease Centre, USA presented by Dr J. Richt,the National Veterinary Services Laboratories, USA presented by Dr M. Hall,the Commissariat à L’Energie Atomique, France presented by Professor C.Lasmezas, the Veterinary Laboratories Agency, UK presented by Dr. L. Terryand the National Institute of Infectious Diseases, Japan provided by Dr Y.Yamakawa.
3Jacobs et al. Molecular discrimination of atypical bovine spongiformencephalopathy strains from a geographical region spanning a wide area ineurope. J Clin Microbiol. 2007;45(6):1821-9.
4Casalone et al. Identification of a second bovine amyloidotic spongiformencephalopathy: molecular similarities with sporadic Creutzfeldt-Jakobdisease. Proc Natl Acad Sci U S A. 2004;101(9):3065-70.
5 Buschmann et al. Atypical BSE in Germany--proof of transmissibility andbiochemical characterization. Vet Microbiol. 2006;117(2-4):103-16.
6Yamakawa et al. Expert Committee for BSE Diagnosis, Ministry of Health,Labour and Welfare of Japan. Atypical proteinase K-resistant prion protein(PrPres) observed in an apparently healthy 23-month-old Holstein steer. JpnJ Infect Dis. 2003;56(5-6):221-2.
7Brown et al. On the question of sporadic or atypical bovine spongiformencephalopathy and Creutzfeldt-Jakob disease. Emerg Infect Dis.200;12(12):1816-21.
8Biacabe et al. Distinct molecular phenotypes in bovine prion diseases. EMBORep. 2004;5(1):110-5.
9Richt et al. Identification and characterisation of two bovine spongiformencephalopathy cases diagnosed in the United States. J Vet Diagn Invest2007;19:142-54
10Capobianco et al. Conversion of the BASE Prion Strain into the BSE Strain:The Origin of BSE? PLoS Pathog. 2007;3(3):e31
11Baron et al. Transmission of new bovine prion to mice. Emerg Infect Dis.2006;12(7):1125-8.
12Beringue et al. Isolation from cattle of a prion strain distinct from thatcausing bovine spongiform encephalopathy. PLoS Pathog. 2006;2(10):e112.
13Beringue et al. A bovine prion acquires an epidemic bovine spongiformencephalopathy strain-like phenotype on interspecies transmission. JNeurosci. 2007;27(26):6965-71.
Page updated: 1 August, 2007
http://www.seac.gov.uk/statements/newforms-bse.htm
Friday, November 30, 2007Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse Model Volume 13, Number 12–December 2007ResearchPhenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse ModelThierry Baron,* Anna Bencsik,* Anne-Gaëlle Biacabe,* Eric Morignat,* andRichard A. Bessen†*Agence Française de Sécurité Sanitaire des Aliments–Lyon, Lyon, France; and†Montana State University, Bozeman, Montana, USA
Abstract
Transmissible mink encepholapathy (TME) is a foodborne transmissiblespongiform encephalopathy (TSE) of ranch-raised mink; infection with aruminant TSE has been proposed as the cause, but the precise origin of TMEis unknown. To compare the phenotypes of each TSE, bovine-passaged TMEisolate and 3 distinct natural bovine spongiform encephalopathy (BSE) agents(typical BSE, H-type BSE, and L-type BSE) were inoculated into an ovinetransgenic mouse line (TgOvPrP4). Transgenic mice were susceptible toinfection with bovine-passaged TME, typical BSE, and L-type BSE but not toH-type BSE. Based on survival periods, brain lesions profiles,disease-associated prion protein brain distribution, and biochemicalproperties of protease-resistant prion protein, typical BSE had a distintphenotype in ovine transgenic mice compared to L-type BSE and bovine TME.The similar phenotypic properties of L-type BSE and bovine TME in TgOvPrP4mice suggest that L-type BSE is a much more likely candidate for the originof TME than is typical BSE.
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Conclusion
These studies provide experimental evidence that the Stetsonville TME agentis distinct from typical BSE but has phenotypic similarities to L-type BSEin TgOvPrP4 mice. Our conclusion is that L-type BSE is a more likelycandidate for a bovine source of TME infection than typical BSE. In thescenario that a ruminant TSE is the source for TME infection in mink, thiswould be a second example of transmission of a TSE from ruminants tonon-ruminants under natural conditions or farming practices in addition totransmission of typical BSE to humans, domestic cats, and exotic zoo animals(37). The potential importance of this finding is relevant to L-type BSE,which based on experimental transmission into humanized PrP transgenic miceand macaques, suggests that L-type BSE is more pathogenic for humans thantypical BSE (24,38).
http://www.cdc.gov/eid/content/13/12/1887.htm?s_cid=eid1887_e
J. Biol. Chem., Vol. 282, Issue 49, 35878-35886, December 7, 2007
High Titers of Transmissible Spongiform Encephalopathy InfectivityAssociated with Extremely Low Levels of PrPSc in Vivo*
Rona M. Barron12, Susan L. Campbell13, Declan King, Anne Bellon, Karen E.Chapman¶, R. Anthony Williamson, and Jean C. MansonFrom the Neuropathogenesis Unit, Roslin Institute, Ogston Building, WestMains Road, Edinburgh EH9 3JF, Scotland, United Kingdom, the Department ofImmunology, Scripps Research Institute, La Jolla, California 92037, and the¶Centre for Cardiovascular Sciences, Queen's Medical Research Institute,University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ,Scotland, United Kingdom
Diagnosis of transmissible spongiform encephalopathy (TSE) disease in humansand ruminants relies on the detection in post-mortem brain tissue of theprotease-resistant form of the host glycoprotein PrP. The presence of thisabnormal isoform (PrPSc) in tissues is taken as indicative of the presenceof TSE infectivity. Here we demonstrate conclusively that high titers of TSEinfectivity can be present in brain tissue of animals that show clinical andvacuolar signs of TSE disease but contain low or undetectable levels ofPrPSc. This work questions the correlation between PrPSc level and the titerof infectivity and shows that tissues containing little or no proteinaseK-resistant PrP can be infectious and harbor high titers of TSE infectivity.Reliance on protease-resistant PrPSc as a sole measure of infectivity maytherefore in some instances significantly underestimate biologicalproperties of diagnostic samples, thereby undermining efforts to contain anderadicate TSEs.
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Received for publication, May 25, 2007 , and in revised form, September 24,2007.
* This work was supported by United Kingdom Department for Environment,Food, and Rural Affairs Grant SE1437. The costs of publication of thisarticle were defrayed in part by the payment of page charges. This articlemust therefore be hereby marked "advertisement" in accordance with 18 U.S.C.Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org)contains/ supplemental Figs. S1–S3 and Table S1.
1 Both authors contributed equally to this work.
3 Current address: Medical Research Council Clinical Sciences Centre,Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, UnitedKingdom.
2 To whom correspondence should be addressed. Tel.: 44-131-667-5204; Fax:44-131-668-3872; E-mail: rona.barron@bbsrc.ac.uk.
http://www.jbc.org/cgi/content/abstract/282/49/35878?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=prion&searchid=1&FIRSTINDEX=0&volume=282&issue=49&resourcetype=HWCIT
Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse Model Volume 13, Number 12–December 2007Research
Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle andL-type Bovine Spongiform Encephalopathy in a Mouse Model
Thierry Baron,* Anna Bencsik,* Anne-Gaëlle Biacabe,* Eric Morignat,* andRichard A. Bessen†*Agence Française de Sécurité Sanitaire des Aliments–Lyon, Lyon, France; and†Montana State University, Bozeman, Montana, USA
Abstract
Transmissible mink encepholapathy (TME) is a foodborne transmissiblespongiform encephalopathy (TSE) of ranch-raised mink; infection with aruminant TSE has been proposed as the cause, but the precise origin of TMEis unknown. To compare the phenotypes of each TSE, bovine-passaged TMEisolate and 3 distinct natural bovine spongiform encephalopathy (BSE) agents(typical BSE, H-type BSE, and L-type BSE) were inoculated into an ovinetransgenic mouse line (TgOvPrP4). Transgenic mice were susceptible toinfection with bovine-passaged TME, typical BSE, and L-type BSE but not toH-type BSE. Based on survival periods, brain lesions profiles,disease-associated prion protein brain distribution, and biochemicalproperties of protease-resistant prion protein, typical BSE had a distintphenotype in ovine transgenic mice compared to L-type BSE and bovine TME.The similar phenotypic properties of L-type BSE and bovine TME in TgOvPrP4mice suggest that L-type BSE is a much more likely candidate for the originof TME than is typical BSE.
snip...
Conclusion
These studies provide experimental evidence that the Stetsonville TME agentis distinct from typical BSE but has phenotypic similarities to L-type BSEin TgOvPrP4 mice. Our conclusion is that L-type BSE is a more likelycandidate for a bovine source of TME infection than typical BSE. In thescenario that a ruminant TSE is the source for TME infection in mink, thiswould be a second example of transmission of a TSE from ruminants tonon-ruminants under natural conditions or farming practices in addition totransmission of typical BSE to humans, domestic cats, and exotic zoo animals(37). The potential importance of this finding is relevant to L-type BSE,which based on experimental transmission into humanized PrP transgenic miceand macaques, suggests that L-type BSE is more pathogenic for humans thantypical BSE (24,38).
http://www.cdc.gov/eid/content/13/12/1887.htm?s_cid=eid1887_e
To be published in the Proceedings of theFourth International Scientific Congress inFur Animal Production. Toronto, Canada,August 21-28, 1988
Evidence That Transmissible Mink EncephalopathyResults from Feeding Infected Cattle
R.F. Marsh* and G.R. Hartsough
•Department of Veterinary Science, University of Wisconsin-Madison, Madison,Wisconsin 53706; and ^Emba/Creat Lakes Ranch Service, Thiensville, Wisconsin53092
OBSERVATIONS AND RESULTS
A New Incidence of TME. In April of 1985, a mink rancher in Stetsonville, Wisconsin reported that many of his mink were "acting funny", and some had died. At this time, we visited the farm and found that approximately 10% of all adult mink were showing typical signs of TME: insidious onset characterized by subtle behavioral changes, loss of normal habits of cleanliness, deposition of droppings throughout the pen rather than in asingle area, hyperexcitability, difficulty in chewing and swallowing, and tails arched overtheir _backs like squirrels. These signs were followed by progressive deterioration ofneurologic function beginning with locomoior incoordination, long periods of somnolencein which the affected mink would stand motionless with its head in the corner of the cage, complete debilitation, and death. Over the next 8-10 weeks, approximately 40% of all the adult mink on the farm died from TME. Since previous incidences of TME were associated with common or shared feeding practices, we obtained a careful history of feed ingredients used over the past 12-18 months. The rancher was a "dead stock" feeder using mostly (>95%) downer or dead dairy cattle and a few horses. Sheep had never been fed.
Experimental Transmission. The clinical diagnosis of TME was confirmed byhistopaihologic examination and by experimental transmission to mink after incubation periods of four months. To investigate the possible involvement of cattle in this diseasecycle, two six-week old castrated Holstein bull calves were inoculated intracerebrally with a brain suspension from affected mink. Each developed a fatal spongiformencephalopathy after incubation periods of 18 and 19 months.
DISCUSSION
These findings suggest that TME may result from feeding mink infected cattle and we have alerted bovine practitioners that there may exist an as yet unrecognized scrapie-like disease of cattle in the United States (Marsh and Hartsough, 1986). A new bovine spongiform encephalopathy has recently been reported in England (Wells et al.,1987), and investigators are presently studying its transmissibility and possiblerelationship to scrapie. Because this new bovine disease in England is characterized bybehavioral changes, hyperexcitability, and agressiveness, it is very likely it would beconfused with rabies in the United Stales and not be diagnosed. Presently, brains from cattle in the United States which are suspected of rabies infection are only tested withanti-rabies virus antibody and are not examined histopathologically for lesions ofspongiform encephalopathy.We are presently pursuing additional studies to further examine the possible involvement of cattle in the epidemiology of TME. One of these is the backpassage of our experimental bovine encephalopathy to mink. Because (here are as yet no agent-specific proteins or nucleic acids identified for these transmissible neuropathogens, one means of distinguishing them is by animal passage and selection of the biotype which grows best in a particular host. This procedure has been used to separate hamster-adapted and mink-udapted TME agents (Marsh and Hanson, 1979). The intracerebral backpassage of the experimental bovine agent resulted in incubations of only four months indicating no de-adaptation of the Stetsonville agent for mink after bovine passage. Mink fed infected bovine brain remain normal after six months. It will be essential to demonstrate oral transmission from bovine to mink it this proposed epidemiologicassociation is to be confirmed.
ACKNOWLEDGEMENTS
MARSH
http://www.bseinquiry.gov.uk/files/mb/m09/tab05.pdf
In Confidence - Perceptions of unconventional slow virus diseasesof animals in the USA - APRIL-MAY 1989 - G A H Wells
http://www.bseinquiry.gov.uk/files/mb/m11b/tab01.pdf
Transmissible Mink Encephalopathy TME
Subject: In Confidence - Perceptions of unconventional slow virus diseasesof animals in the USA - APRIL-MAY 1989 - G A H Wells
Gerald Wells: Report of the Visit to USA, April-May 1989
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The general opinion of those present was that BSE, as anovert disease phenomenon, _could exist in the USA, but if it did,it was very rare. The need for improved and specific surveillancemethods to detect it as recognised...
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It is clear that USDA have little information and _no_ regulatoryresponsibility for rendering plants in the US...
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3. Prof. A. Robertson gave a brief account of BSE. The US approachwas to accord it a _very low profile indeed_. Dr. A Thiermann showedthe picture in the ''Independent'' with cattle being incinerated and thoughtthis was a fanatical incident to be _avoided_ in the US _at all costs_...(and they weren't kidding...tss)
snip...please read this old full text document !
http://www.bseinquiry.gov.uk/files/mb/m11b/tab01.pdf
Subject: TME hyper/drowsy, INTER-SPECIES TRANSMISSION CWD and strain properties
Date: October 22, 2007 at 12:48 pm PST
Completely Edited Version
PRION ROUNDTABLE
TME hyper/drowsy, INTER-SPECIES TRANSMISSION CWD and strain properties
page 19 of 62. ...tss
Dr. Detwiler: How would you explain that biochemically?
Dr. Bartz: When PRPC is converted to PRPSC, it's misfolded. There have to be many different stable energy states for the misfolded protein. I would hypothesize that mink PRPSC, when it interacts with hamster PRPC, it can fold into several different stable PRPSC molecules. So initially you get the mink interacting with hamster, and then you get a strain produced. I think early on in those first few rounds of replication, whatever strain isproduced is probably going to be the predominant one because it has a jumpstart on the rest of them. On this really complicated western blot, we are mixing hyper and drowsy at known ratios, and basically we can mimic the see ffects. So it really is the ratio of hyper/drowsy produced by interspecies transmission that's causing this sort of effect.
To summarize inter-species transmission, we have PRPSC interacting with the new host PRPC molecule to change it into PRPSC. We think that, in certain instances, multiple strains can be produced. Intra-species transmission results in competition between these strains and eventual emergence of a predominant strain. We think the initial ratio of strains is important and affects this whole passage history. Probably the replication properties ofstrains is important. We think that drowsy is the predominant strain produced, but hyper replicates so much faster, it has an advantage.
One really important thing I want to point out here is that strain properties can change upon inter-species transmission. Chronic wasting disease doesn't cause disease when you passage it in a hamster, but if you passage CWD into ferrets, and then take that ferret passage tissue, it can cause disease in hamsters. So inter-species transmission can expand the hos trange. Also, with the hyper and drowsy, the more hamster passages you do, if you back-passage the inoculum into mink, hyper loses pathogenicity for mink quite quickly, where drowsy retains pathogenicity for mink.The important point I want to make is that, when you're assessing inter-species transmission and you do a transmission study and it's negative, you have to be careful in saying it's negative for the strains you looked at. With this example, it's clear you could take hyper TME, inoculate mink, and they don't come down with the disease, so you might assume hamster prions don't cause disease in mink. That strain doesn't. You have to b ecareful assessing negative transmission results based on what's known about the strain properties.
The last thing I want to talk about is persistence. This would be the case where PRPSC interacts with the host PRPC and you get really slow replication. The replication agent is so slow that the animal dies of old age before clinical signs can occur.
This study is from Rick Race at NIH, transmitting hamster PRPSC into mice.He collected animals post-infection out to 782 days. None of these animals had clinical signs of prion disease, which is consistent with everything we knew about this species barrier. But when he went back and looked for PRP residue in these animals, he couldn't detect hamster PRP residue, but in a few of these animals with very long times post-infection, he could detect mouse PRP residue.
When he did the second passage, into either hamsters or mice, clinical signs appeared in the second passage. The point is that first inter-species transmission may not cause clinical signs, but you still can get replication to agent that subsequently, when you passage it into the same host species, results in clinical signs of the disease.
In the cell-free conversion studies, hamster PRPSC could not convert mouse PRPSC. Every sort of assay has limitations. The cell-free conversion said it couldn’t replicate. It could, but it was so slow and so long that the assay could not detect them.
I think persistence is very important. If you have inter-species transmission occurring and it doesn't cause clinical disease, and if you take the tissue and keep feeding it to that same host species, you’re going to get amplification and potentially emergence of the disease.
Is PRPSC shed in the environment? I have no idea. Terry can talk about that.Does PRPSC survive in the environment? The studies on deer PRPSC have not been done, but if deer PRPSC behaves like any other PRPSC, yes it can survive in the environment. Can PRPSC reach a new host species? I don'tknow. If they share common pastures, it's a possibility. Can PRPSC get to the central nervous system? Clearly, cattle are susceptible to oral infection, so that's yes. Can deer PRPSC convert cattle PRPC to the host PRPSC? Self-reconversion experiments would say yes, but very inefficiently. But really, the gold standard is the transmission studies, and there are two of these ongoing right now. One is at the USDA at Ames, and this is intra-cerebral inoculation. They are susceptible to IC infections. This means that once the agent reaches the brain, it can cause disease, but obviously in the field, that's not the natural route. Beth Williams is doing some oral infection studies, but I'm not sure of the status of those.
Dr. Thornsberry: So what you’re saying is that, inter-cerebrally, we can get CWD/PRPSC conversion, but that has not occurred, to anyone's knowledge, in the natural route.
Dr. Bartz: Right. IC inoculation is used because it has a short incubationperiod. It only tells us that replication can occur once the agent reaches the brain.
Dr. Thornsberry: Let's hypothesize that I had some cattle on the eastern slope and they were in the same pasture with elk with CWD. If a cow had been exposed to the PRP Scrapie and it did develop disease four years later, would that look like BSE? Would there be a way to determine if it came from CWD?
Dr. Bartz: The IC studies in cattle indicate it does not look like BSE. The clinical signs of the IC/CWD cattle are more like downer cattle, and not aggressive. As far as finding the source of a bovine TSE, the gold standard is the lesion profile study where you take cattle tissue and inoculate it into mice with appropriate controls, wait until the mice come down, and do the lesion profiling.
Dr. Thornsberry: There were two cases in Japan, but they indicated that tissue was not classical BSE as seen in Europe. Have you heard anything about that?
Dr. Bartz: This is based on differences on migration and the glycoform ratio of PrPSc.
Dr. Detwiler: Canada based that question because the herd that that animal came from was in Saskatchewan, in an area with CWD. That was one of the questions they faced right off the bat: is this BSE or is this some kind of transmission from CWD-infected elk in the area? Not only the histological lesions were classic BSE lesions, but clinically it's very difficult because if you miss the other behavioral changes, which this owner did. It was someone who had been a catfish farmer. He missed the early signs. The animal presented to slaughter as a down animal, non-responsive. Clinically it looked like just a down cow, but they did send that on to the United Kingdom and they did do some comparison glycoform patterns. Those haven’t been validated, but at least on preliminary work, it looked like classical BSE.
The Japanese case was a 23-month-old which was born in October. Their scientists say the western blot pattern looked different. The most recent case, which was a 21-month-old, looked more like classic BSE. The Italian cases were older animals, 15 and 16 years of age. But is it methodology? Is it really standard? That has to be sorted out before too much can be said.
Dr. Bartz: Glycoform ratio is dependent on very technical matters, what antibodies you use, what detection system you use. Those have to be standardized before you can start comparing from one lab to another.
Dr. Detwiler: The Japanese used a western blot they'd developed in their lab. It can't be compared across laboratories.
Dr. Bartz: That's problematic.
Accomplished this day, Wednesday, December 11, 2003, Denver, Colorado
The roundtable presentations and discussions were recorded. A transcript will be made availableto the Academy of Veterinary Consultants, theAmerican Association of Bovine Practitioners, and the Colleges of Veterinary Medicine throughout theUnited States and Canada. A condensed version translated for the livestock industry will be made available to educate livestock producers about prion related diseases.
http://www.r-calfusa.com/Newsletter/2004January.pdf
SEE FULL TEXT TME
http://transmissible-mink-encephalopathy.blogspot.com/
NOR-98 ATYPICAL SCRAPIE USA UPDATE AS AT OCT 2007
http://nor-98.blogspot.com/
USA BASE CASE, (ATYPICAL BSE), AND OR TSE (whatever they are calling it today), please note that both the ALABAMA COW, AND THE TEXAS COW, both were ''H-TYPE'', personal communication Detwiler et al Wednesday, August 22, 2007 11:52 PM. ...TSS
TEXAS AND ALABAMA MAD COW CASES
http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0703&L=sanet-mg&T=0&P=8125
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease inthe United States
http://cjdusa.blogspot.com/
TSS
Subject: SEAC New forms of Bovine Spongiform Encephalopathy 1 August 2007Date: August 5, 2007 at 10:41 am PST
SEAC
Position Statement
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New forms of Bovine Spongiform Encephalopathy
Issue
1. SEAC considered the implications of scientific research on recentlyidentified novel forms of bovine spongiform encephalopathy (BSE).
Background
2. Very low numbers of cattle with abnormal prion proteins (PrPsc) withdifferent biochemical properties from those normally associated with BSEhave been detected in active surveillance programmes in a number ofcountries. SEAC considered (SEAC 97, May 2007) published and unpublishedresearch relating to these putatively new forms of BSE.
Characterisation of cases
3. Different forms of BSE were initially identified and distinguished fromclassical BSE on the basis of their PrPsc profiles in biochemical tests. AllBSE cases identified to date conform to one of three different PrPscprofiles on western blot tests. The European Union (EU) Community ReferenceLaboratory has suggested that cases be classified on the basis of theseprofiles as classical, L- or H-type BSE. The key distinguishing features inwestern blot tests are the lower concentration of the diglycosylated bandand the slightly lower molecular mass of unglycosylated band of PrPsc inL-type BSE, and the higher molecular mass of the unglycosylated band inH-type BSE, compared with classical BSE. A western blot method todiscriminate between the three types of BSE has been developed .
4. All the reported cases of L-4,5,6,7 and H-type7,9,8,9 BSE have beendetected during active surveillance of healthy slaughtered animals or fallenstock. In the majority of cases, retrospective investigations indicated thatthese animals either showed no clinical signs of BSE or showed non-specificsigns such as ataxia and recumbency. As these cases have been detectedfollowing active rather than passive surveillance, it has not been possibleto observe the clinical signs associated with L- or H-type BSE in sufficientdetail to assess whether there are differences in the clinical featuresbetween L-type, H-type and classical BSE. However, a significant distinctionbetween classical BSE and L- and H-type BSEs is the age distribution ofcases as L- and H-type BSE are found in older cattle with an age range of5.5 to 19 years. One putative L-type BSE case was aged two years6, howeverthe BSE typing of this case has not been verified. Around 85% of L- orH-type BSE cases have been found in animals more than 10 years old, which ismuch older than most cases of classical BSE.
5. Neuropathological investigations suggest that PrPsc may be more widelydistributed, with a different brain distribution pattern for L- and H-typeBSE, compared with classical BSE. However, these investigations are limitedby the very low number of animals for which a complete brain has beenavailable for analysis. There are no data on the peripheral distribution ofPrPsc or infectivity of L- and H-type BSE or on the pathogenesis of thesediseases. However, studies to assess the tissue distribution of infectivityand PrPsc in animals throughout the incubation period followingintracerebral challenge are underway.
Prevalence
6. As there is no regulatory requirement to specify the type of BSE whennotifying the EU or the World Organisation of Animal Health of BSE cases, itis not possible to accurately quantify the number of H- or L-type BSE casesthat have occurred world-wide. Information presented to SEAC indicated thatat least 37 cases of L- and H-type BSE have been identified world-wide todate. These cases are widely distributed geographically with L-type casesidentified in a number of European countries and Japan, and H-type casesidentified in a number of European countries and North America.
7. Due to the different approaches to surveillance between countries,proportions of animals tested and methods used, which do not necessarilyinclude systematic molecular typing, these surveillance systems are notequally capable of detecting L- and H-type BSE. Furthermore, surveillanceprocedures, including the most appropriate brain region to sample, have notbeen optimised for the detection of L- and H-type BSE. Therefore, it is notpossible to accurately assess and compare the prevalence of L- and H-typeBSE in different countries. Origins and Causes
8. It is not known whether L- or H-type BSE are newly emerging forms of BSEor whether they have existed for some time and have only come to lightfollowing extensive active surveillance programmes in the EU and elsewhere,together with the introduction and development of new biochemical tests.Studies using historic frozen brain samples from cattle collected frompassive surveillance during the early years of the UK BSE epidemic areunderway to investigate whether L- and H-type BSE existed in the UK in thepast. However, if the prevalence of these BSE types was low, these studiesmay not identify many, if any, cases.
9. Genetic analyses of a few L- and H-type BSE cases4,5,8,9 have notidentified associations between the occurrence of such cases and knowngenetic polymorphisms in the prion protein gene. There are no mutations inthe prion protein gene open reading frame in all, but one, sequenced case.However, the analyses conducted to date are limited by the small number ofcases and controls analysed. Thus, a genetic cause of the disease cannot beruled out.
10. No detailed epidemiological investigations have been conducted toinvestigate the possible causes for, or links between, L- and H-type BSEcases. No geographical clusters of L- and H-type BSE cases have been foundto date. Therefore, it is not possible to rule out feed related,environmental or spontaneous causes for these types of cases.
Transmission studies
11. Transmission studies5,10,11 have demonstrated that both L- and H-typeBSE are transmissible to other species by the intracerebral route. Nostudies have assessed the transmissibility by the oral route. Thus, theavailable information shows that it is possible for species other thancattle to develop these diseases upon infection. However, these data do notallow an assessment of the susceptibility to infection from the most likelynatural route of exposure.
12. L-type BSE has been transmitted to wild-type, bovinised, ovinised andhumanised mice as well as to cattle and a cynomolgus macaque byintracerebral inoculation. Incubation periods, clinical signs,neuropathology as well as the neurological distribution of PrPsc weredistinct from classical BSE13,12. With the exception of transmissions towild-type mice, primary transmissions resulted in clinical disease. Althoughprimary transmission to wild-type mice did not result in clinical disease,secondary transmissions from some of these animals resulted in clinicaldisease. Sub-passage of L-type BSE in wild-type12 and ovinised mice13suggests that L-type BSE may be converted to an infection of a similarphenotype to classical BSE. However, further experiments using serialsub-passages of infections in a range of species are required to more fullyinvestigate whether L-type BSE may convert to a disease with a classical BSEphenotype.
13. H-type BSE has been transmitted to wild type, bovinised and ovinisedmice by intracerebral inoculation with incubation periods, neuropathologyand neurological distribution of PrPsc distinct from classical and L-typeBSE.
14. Studies of intracerebral transmission of H-type BSE to cattle andcynomolgus macaques . To date, clinical disease has developed from oneintracerebral inoculation of H-type BSE to cattle. Oral transmissions of L-and H-type to cynomolgus macaques are underway.
Human and animals health implications15. There are too few data to enable an assessment of the naturaltransmissibility of L- and H-type BSE between cattle, or to sheep or goats.The present feed control measures which prevent feeding of mammalian meatand bone meal to ruminants would limit the spread of these forms of BSE tocattle, sheep and goats should they be transmissible to these species by theoral route.
16. Similarly, the lack of data on the oral transmissibility of L- or H-typeBSE to humanised mice or non-human primates does not allow an assessment ofthe human health implications of ingestion of meat from animals infectedwith L- or H-type BSE. The differing clinical features of L-type andclassical BSE in the cynomolgus macaque suggest that if L-type BSE were everto be transmitted to humans, its clinical presentation may differ from thatof vCJD. It is possible, therefore, that, if transmitted to humans, it couldbe identified by continuing surveillance of unusual neurological conditionsin place in the UK.
Conclusions
17. L- and H-type BSE have not yet been fully characterised, however datafrom biochemical, neuropathological and transmission studies suggest that L-and H-type and classical BSE may be distinct strains of prion disease. Incontrast to classical BSE, L- and H-type BSE infections are mostly detectedin animals of older age with most of the infected animals identified to dateover 10 years of age. Although L- and H-type BSE may be diseases thatpredominantly affect older cattle, it is possible that infections may occurat a young age and develop over a long period of time. The origins andpossible routes of transmission, if transmissible under natural conditions,of L- and H-type BSE are not known. Due to the older age of the casesidentified, wide geographical distribution and their apparent low number, itis possible they may have arisen spontaneously, however feed borne orenvironmental transmission cannot be ruled out.
18. As data on the oral transmissibility of L- and H-type BSE are lacking,it is not possible to fully assess the animal and human health implications.However, as the occurrence of L- and H-type BSE appears to be low, and dueto the feed control measures in place, the risk of spread to other cattle,sheep and goats is likely to be very low assuming that, as with classicalBSE, environmental transmission is negligible. For these reasons, andbecause of the BSE control measures in place to protect the food supply,assuming that the specific risk material controls are similarly effectivefor L- and H-type and classical BSE, the risk to human health is likely tobe very low to negligible. However, given the paucity of data on L- andH-type BSE, a close watching brief should be maintained on the findings ofresearch in this area.
SEAC July 2007
References
1SEAC 97 discussion papers available at
http://www.seac.gov.uk/agenda/agen100507.htm
2Published and unpublished data from the Institute for Novel and EmergingInfectious Diseases, Germany presented by Dr M. Groschup, the InstitutoNazionale Neurologico, Italy presented by Dr F. Tagliavini, the Unite AgentsTransmissibles Non Conventionnels, France presented by Dr T. Baron, theIstituto Zooprofilattico Sperimentale del Piemonte, Italy presented by Dr P.Acutis, the National Animal Disease Centre, USA presented by Dr J. Richt,the National Veterinary Services Laboratories, USA presented by Dr M. Hall,the Commissariat à L’Energie Atomique, France presented by Professor C.Lasmezas, the Veterinary Laboratories Agency, UK presented by Dr. L. Terryand the National Institute of Infectious Diseases, Japan provided by Dr Y.Yamakawa.
3Jacobs et al. Molecular discrimination of atypical bovine spongiformencephalopathy strains from a geographical region spanning a wide area ineurope. J Clin Microbiol. 2007;45(6):1821-9.
4Casalone et al. Identification of a second bovine amyloidotic spongiformencephalopathy: molecular similarities with sporadic Creutzfeldt-Jakobdisease. Proc Natl Acad Sci U S A. 2004;101(9):3065-70.
5 Buschmann et al. Atypical BSE in Germany--proof of transmissibility andbiochemical characterization. Vet Microbiol. 2006;117(2-4):103-16.
6Yamakawa et al. Expert Committee for BSE Diagnosis, Ministry of Health,Labour and Welfare of Japan. Atypical proteinase K-resistant prion protein(PrPres) observed in an apparently healthy 23-month-old Holstein steer. JpnJ Infect Dis. 2003;56(5-6):221-2.
7Brown et al. On the question of sporadic or atypical bovine spongiformencephalopathy and Creutzfeldt-Jakob disease. Emerg Infect Dis.200;12(12):1816-21.
8Biacabe et al. Distinct molecular phenotypes in bovine prion diseases. EMBORep. 2004;5(1):110-5.
9Richt et al. Identification and characterisation of two bovine spongiformencephalopathy cases diagnosed in the United States. J Vet Diagn Invest2007;19:142-54
10Capobianco et al. Conversion of the BASE Prion Strain into the BSE Strain:The Origin of BSE? PLoS Pathog. 2007;3(3):e31
11Baron et al. Transmission of new bovine prion to mice. Emerg Infect Dis.2006;12(7):1125-8.
12Beringue et al. Isolation from cattle of a prion strain distinct from thatcausing bovine spongiform encephalopathy. PLoS Pathog. 2006;2(10):e112.
13Beringue et al. A bovine prion acquires an epidemic bovine spongiformencephalopathy strain-like phenotype on interspecies transmission. JNeurosci. 2007;27(26):6965-71.
Page updated: 1 August, 2007
http://www.seac.gov.uk/statements/newforms-bse.htm
Friday, November 30, 2007Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse Model Volume 13, Number 12–December 2007ResearchPhenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse ModelThierry Baron,* Anna Bencsik,* Anne-Gaëlle Biacabe,* Eric Morignat,* andRichard A. Bessen†*Agence Française de Sécurité Sanitaire des Aliments–Lyon, Lyon, France; and†Montana State University, Bozeman, Montana, USA
Abstract
Transmissible mink encepholapathy (TME) is a foodborne transmissiblespongiform encephalopathy (TSE) of ranch-raised mink; infection with aruminant TSE has been proposed as the cause, but the precise origin of TMEis unknown. To compare the phenotypes of each TSE, bovine-passaged TMEisolate and 3 distinct natural bovine spongiform encephalopathy (BSE) agents(typical BSE, H-type BSE, and L-type BSE) were inoculated into an ovinetransgenic mouse line (TgOvPrP4). Transgenic mice were susceptible toinfection with bovine-passaged TME, typical BSE, and L-type BSE but not toH-type BSE. Based on survival periods, brain lesions profiles,disease-associated prion protein brain distribution, and biochemicalproperties of protease-resistant prion protein, typical BSE had a distintphenotype in ovine transgenic mice compared to L-type BSE and bovine TME.The similar phenotypic properties of L-type BSE and bovine TME in TgOvPrP4mice suggest that L-type BSE is a much more likely candidate for the originof TME than is typical BSE.
snip...
Conclusion
These studies provide experimental evidence that the Stetsonville TME agentis distinct from typical BSE but has phenotypic similarities to L-type BSEin TgOvPrP4 mice. Our conclusion is that L-type BSE is a more likelycandidate for a bovine source of TME infection than typical BSE. In thescenario that a ruminant TSE is the source for TME infection in mink, thiswould be a second example of transmission of a TSE from ruminants tonon-ruminants under natural conditions or farming practices in addition totransmission of typical BSE to humans, domestic cats, and exotic zoo animals(37). The potential importance of this finding is relevant to L-type BSE,which based on experimental transmission into humanized PrP transgenic miceand macaques, suggests that L-type BSE is more pathogenic for humans thantypical BSE (24,38).
http://www.cdc.gov/eid/content/13/12/1887.htm?s_cid=eid1887_e
J. Biol. Chem., Vol. 282, Issue 49, 35878-35886, December 7, 2007
High Titers of Transmissible Spongiform Encephalopathy InfectivityAssociated with Extremely Low Levels of PrPSc in Vivo*
Rona M. Barron12, Susan L. Campbell13, Declan King, Anne Bellon, Karen E.Chapman¶, R. Anthony Williamson, and Jean C. MansonFrom the Neuropathogenesis Unit, Roslin Institute, Ogston Building, WestMains Road, Edinburgh EH9 3JF, Scotland, United Kingdom, the Department ofImmunology, Scripps Research Institute, La Jolla, California 92037, and the¶Centre for Cardiovascular Sciences, Queen's Medical Research Institute,University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ,Scotland, United Kingdom
Diagnosis of transmissible spongiform encephalopathy (TSE) disease in humansand ruminants relies on the detection in post-mortem brain tissue of theprotease-resistant form of the host glycoprotein PrP. The presence of thisabnormal isoform (PrPSc) in tissues is taken as indicative of the presenceof TSE infectivity. Here we demonstrate conclusively that high titers of TSEinfectivity can be present in brain tissue of animals that show clinical andvacuolar signs of TSE disease but contain low or undetectable levels ofPrPSc. This work questions the correlation between PrPSc level and the titerof infectivity and shows that tissues containing little or no proteinaseK-resistant PrP can be infectious and harbor high titers of TSE infectivity.Reliance on protease-resistant PrPSc as a sole measure of infectivity maytherefore in some instances significantly underestimate biologicalproperties of diagnostic samples, thereby undermining efforts to contain anderadicate TSEs.
---------------------------------------------
Received for publication, May 25, 2007 , and in revised form, September 24,2007.
* This work was supported by United Kingdom Department for Environment,Food, and Rural Affairs Grant SE1437. The costs of publication of thisarticle were defrayed in part by the payment of page charges. This articlemust therefore be hereby marked "advertisement" in accordance with 18 U.S.C.Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org)contains/ supplemental Figs. S1–S3 and Table S1.
1 Both authors contributed equally to this work.
3 Current address: Medical Research Council Clinical Sciences Centre,Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, UnitedKingdom.
2 To whom correspondence should be addressed. Tel.: 44-131-667-5204; Fax:44-131-668-3872; E-mail: rona.barron@bbsrc.ac.uk.
http://www.jbc.org/cgi/content/abstract/282/49/35878?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=prion&searchid=1&FIRSTINDEX=0&volume=282&issue=49&resourcetype=HWCIT
Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse Model Volume 13, Number 12–December 2007Research
Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle andL-type Bovine Spongiform Encephalopathy in a Mouse Model
Thierry Baron,* Anna Bencsik,* Anne-Gaëlle Biacabe,* Eric Morignat,* andRichard A. Bessen†*Agence Française de Sécurité Sanitaire des Aliments–Lyon, Lyon, France; and†Montana State University, Bozeman, Montana, USA
Abstract
Transmissible mink encepholapathy (TME) is a foodborne transmissiblespongiform encephalopathy (TSE) of ranch-raised mink; infection with aruminant TSE has been proposed as the cause, but the precise origin of TMEis unknown. To compare the phenotypes of each TSE, bovine-passaged TMEisolate and 3 distinct natural bovine spongiform encephalopathy (BSE) agents(typical BSE, H-type BSE, and L-type BSE) were inoculated into an ovinetransgenic mouse line (TgOvPrP4). Transgenic mice were susceptible toinfection with bovine-passaged TME, typical BSE, and L-type BSE but not toH-type BSE. Based on survival periods, brain lesions profiles,disease-associated prion protein brain distribution, and biochemicalproperties of protease-resistant prion protein, typical BSE had a distintphenotype in ovine transgenic mice compared to L-type BSE and bovine TME.The similar phenotypic properties of L-type BSE and bovine TME in TgOvPrP4mice suggest that L-type BSE is a much more likely candidate for the originof TME than is typical BSE.
snip...
Conclusion
These studies provide experimental evidence that the Stetsonville TME agentis distinct from typical BSE but has phenotypic similarities to L-type BSEin TgOvPrP4 mice. Our conclusion is that L-type BSE is a more likelycandidate for a bovine source of TME infection than typical BSE. In thescenario that a ruminant TSE is the source for TME infection in mink, thiswould be a second example of transmission of a TSE from ruminants tonon-ruminants under natural conditions or farming practices in addition totransmission of typical BSE to humans, domestic cats, and exotic zoo animals(37). The potential importance of this finding is relevant to L-type BSE,which based on experimental transmission into humanized PrP transgenic miceand macaques, suggests that L-type BSE is more pathogenic for humans thantypical BSE (24,38).
http://www.cdc.gov/eid/content/13/12/1887.htm?s_cid=eid1887_e
To be published in the Proceedings of theFourth International Scientific Congress inFur Animal Production. Toronto, Canada,August 21-28, 1988
Evidence That Transmissible Mink EncephalopathyResults from Feeding Infected Cattle
R.F. Marsh* and G.R. Hartsough
•Department of Veterinary Science, University of Wisconsin-Madison, Madison,Wisconsin 53706; and ^Emba/Creat Lakes Ranch Service, Thiensville, Wisconsin53092
OBSERVATIONS AND RESULTS
A New Incidence of TME. In April of 1985, a mink rancher in Stetsonville, Wisconsin reported that many of his mink were "acting funny", and some had died. At this time, we visited the farm and found that approximately 10% of all adult mink were showing typical signs of TME: insidious onset characterized by subtle behavioral changes, loss of normal habits of cleanliness, deposition of droppings throughout the pen rather than in asingle area, hyperexcitability, difficulty in chewing and swallowing, and tails arched overtheir _backs like squirrels. These signs were followed by progressive deterioration ofneurologic function beginning with locomoior incoordination, long periods of somnolencein which the affected mink would stand motionless with its head in the corner of the cage, complete debilitation, and death. Over the next 8-10 weeks, approximately 40% of all the adult mink on the farm died from TME. Since previous incidences of TME were associated with common or shared feeding practices, we obtained a careful history of feed ingredients used over the past 12-18 months. The rancher was a "dead stock" feeder using mostly (>95%) downer or dead dairy cattle and a few horses. Sheep had never been fed.
Experimental Transmission. The clinical diagnosis of TME was confirmed byhistopaihologic examination and by experimental transmission to mink after incubation periods of four months. To investigate the possible involvement of cattle in this diseasecycle, two six-week old castrated Holstein bull calves were inoculated intracerebrally with a brain suspension from affected mink. Each developed a fatal spongiformencephalopathy after incubation periods of 18 and 19 months.
DISCUSSION
These findings suggest that TME may result from feeding mink infected cattle and we have alerted bovine practitioners that there may exist an as yet unrecognized scrapie-like disease of cattle in the United States (Marsh and Hartsough, 1986). A new bovine spongiform encephalopathy has recently been reported in England (Wells et al.,1987), and investigators are presently studying its transmissibility and possiblerelationship to scrapie. Because this new bovine disease in England is characterized bybehavioral changes, hyperexcitability, and agressiveness, it is very likely it would beconfused with rabies in the United Stales and not be diagnosed. Presently, brains from cattle in the United States which are suspected of rabies infection are only tested withanti-rabies virus antibody and are not examined histopathologically for lesions ofspongiform encephalopathy.We are presently pursuing additional studies to further examine the possible involvement of cattle in the epidemiology of TME. One of these is the backpassage of our experimental bovine encephalopathy to mink. Because (here are as yet no agent-specific proteins or nucleic acids identified for these transmissible neuropathogens, one means of distinguishing them is by animal passage and selection of the biotype which grows best in a particular host. This procedure has been used to separate hamster-adapted and mink-udapted TME agents (Marsh and Hanson, 1979). The intracerebral backpassage of the experimental bovine agent resulted in incubations of only four months indicating no de-adaptation of the Stetsonville agent for mink after bovine passage. Mink fed infected bovine brain remain normal after six months. It will be essential to demonstrate oral transmission from bovine to mink it this proposed epidemiologicassociation is to be confirmed.
ACKNOWLEDGEMENTS
MARSH
http://www.bseinquiry.gov.uk/files/mb/m09/tab05.pdf
In Confidence - Perceptions of unconventional slow virus diseasesof animals in the USA - APRIL-MAY 1989 - G A H Wells
http://www.bseinquiry.gov.uk/files/mb/m11b/tab01.pdf
Transmissible Mink Encephalopathy TME
Subject: In Confidence - Perceptions of unconventional slow virus diseasesof animals in the USA - APRIL-MAY 1989 - G A H Wells
Gerald Wells: Report of the Visit to USA, April-May 1989
snip...
The general opinion of those present was that BSE, as anovert disease phenomenon, _could exist in the USA, but if it did,it was very rare. The need for improved and specific surveillancemethods to detect it as recognised...
snip...
It is clear that USDA have little information and _no_ regulatoryresponsibility for rendering plants in the US...
snip...
3. Prof. A. Robertson gave a brief account of BSE. The US approachwas to accord it a _very low profile indeed_. Dr. A Thiermann showedthe picture in the ''Independent'' with cattle being incinerated and thoughtthis was a fanatical incident to be _avoided_ in the US _at all costs_...(and they weren't kidding...tss)
snip...please read this old full text document !
http://www.bseinquiry.gov.uk/files/mb/m11b/tab01.pdf
Subject: TME hyper/drowsy, INTER-SPECIES TRANSMISSION CWD and strain properties
Date: October 22, 2007 at 12:48 pm PST
Completely Edited Version
PRION ROUNDTABLE
TME hyper/drowsy, INTER-SPECIES TRANSMISSION CWD and strain properties
page 19 of 62. ...tss
Dr. Detwiler: How would you explain that biochemically?
Dr. Bartz: When PRPC is converted to PRPSC, it's misfolded. There have to be many different stable energy states for the misfolded protein. I would hypothesize that mink PRPSC, when it interacts with hamster PRPC, it can fold into several different stable PRPSC molecules. So initially you get the mink interacting with hamster, and then you get a strain produced. I think early on in those first few rounds of replication, whatever strain isproduced is probably going to be the predominant one because it has a jumpstart on the rest of them. On this really complicated western blot, we are mixing hyper and drowsy at known ratios, and basically we can mimic the see ffects. So it really is the ratio of hyper/drowsy produced by interspecies transmission that's causing this sort of effect.
To summarize inter-species transmission, we have PRPSC interacting with the new host PRPC molecule to change it into PRPSC. We think that, in certain instances, multiple strains can be produced. Intra-species transmission results in competition between these strains and eventual emergence of a predominant strain. We think the initial ratio of strains is important and affects this whole passage history. Probably the replication properties ofstrains is important. We think that drowsy is the predominant strain produced, but hyper replicates so much faster, it has an advantage.
One really important thing I want to point out here is that strain properties can change upon inter-species transmission. Chronic wasting disease doesn't cause disease when you passage it in a hamster, but if you passage CWD into ferrets, and then take that ferret passage tissue, it can cause disease in hamsters. So inter-species transmission can expand the hos trange. Also, with the hyper and drowsy, the more hamster passages you do, if you back-passage the inoculum into mink, hyper loses pathogenicity for mink quite quickly, where drowsy retains pathogenicity for mink.The important point I want to make is that, when you're assessing inter-species transmission and you do a transmission study and it's negative, you have to be careful in saying it's negative for the strains you looked at. With this example, it's clear you could take hyper TME, inoculate mink, and they don't come down with the disease, so you might assume hamster prions don't cause disease in mink. That strain doesn't. You have to b ecareful assessing negative transmission results based on what's known about the strain properties.
The last thing I want to talk about is persistence. This would be the case where PRPSC interacts with the host PRPC and you get really slow replication. The replication agent is so slow that the animal dies of old age before clinical signs can occur.
This study is from Rick Race at NIH, transmitting hamster PRPSC into mice.He collected animals post-infection out to 782 days. None of these animals had clinical signs of prion disease, which is consistent with everything we knew about this species barrier. But when he went back and looked for PRP residue in these animals, he couldn't detect hamster PRP residue, but in a few of these animals with very long times post-infection, he could detect mouse PRP residue.
When he did the second passage, into either hamsters or mice, clinical signs appeared in the second passage. The point is that first inter-species transmission may not cause clinical signs, but you still can get replication to agent that subsequently, when you passage it into the same host species, results in clinical signs of the disease.
In the cell-free conversion studies, hamster PRPSC could not convert mouse PRPSC. Every sort of assay has limitations. The cell-free conversion said it couldn’t replicate. It could, but it was so slow and so long that the assay could not detect them.
I think persistence is very important. If you have inter-species transmission occurring and it doesn't cause clinical disease, and if you take the tissue and keep feeding it to that same host species, you’re going to get amplification and potentially emergence of the disease.
Is PRPSC shed in the environment? I have no idea. Terry can talk about that.Does PRPSC survive in the environment? The studies on deer PRPSC have not been done, but if deer PRPSC behaves like any other PRPSC, yes it can survive in the environment. Can PRPSC reach a new host species? I don'tknow. If they share common pastures, it's a possibility. Can PRPSC get to the central nervous system? Clearly, cattle are susceptible to oral infection, so that's yes. Can deer PRPSC convert cattle PRPC to the host PRPSC? Self-reconversion experiments would say yes, but very inefficiently. But really, the gold standard is the transmission studies, and there are two of these ongoing right now. One is at the USDA at Ames, and this is intra-cerebral inoculation. They are susceptible to IC infections. This means that once the agent reaches the brain, it can cause disease, but obviously in the field, that's not the natural route. Beth Williams is doing some oral infection studies, but I'm not sure of the status of those.
Dr. Thornsberry: So what you’re saying is that, inter-cerebrally, we can get CWD/PRPSC conversion, but that has not occurred, to anyone's knowledge, in the natural route.
Dr. Bartz: Right. IC inoculation is used because it has a short incubationperiod. It only tells us that replication can occur once the agent reaches the brain.
Dr. Thornsberry: Let's hypothesize that I had some cattle on the eastern slope and they were in the same pasture with elk with CWD. If a cow had been exposed to the PRP Scrapie and it did develop disease four years later, would that look like BSE? Would there be a way to determine if it came from CWD?
Dr. Bartz: The IC studies in cattle indicate it does not look like BSE. The clinical signs of the IC/CWD cattle are more like downer cattle, and not aggressive. As far as finding the source of a bovine TSE, the gold standard is the lesion profile study where you take cattle tissue and inoculate it into mice with appropriate controls, wait until the mice come down, and do the lesion profiling.
Dr. Thornsberry: There were two cases in Japan, but they indicated that tissue was not classical BSE as seen in Europe. Have you heard anything about that?
Dr. Bartz: This is based on differences on migration and the glycoform ratio of PrPSc.
Dr. Detwiler: Canada based that question because the herd that that animal came from was in Saskatchewan, in an area with CWD. That was one of the questions they faced right off the bat: is this BSE or is this some kind of transmission from CWD-infected elk in the area? Not only the histological lesions were classic BSE lesions, but clinically it's very difficult because if you miss the other behavioral changes, which this owner did. It was someone who had been a catfish farmer. He missed the early signs. The animal presented to slaughter as a down animal, non-responsive. Clinically it looked like just a down cow, but they did send that on to the United Kingdom and they did do some comparison glycoform patterns. Those haven’t been validated, but at least on preliminary work, it looked like classical BSE.
The Japanese case was a 23-month-old which was born in October. Their scientists say the western blot pattern looked different. The most recent case, which was a 21-month-old, looked more like classic BSE. The Italian cases were older animals, 15 and 16 years of age. But is it methodology? Is it really standard? That has to be sorted out before too much can be said.
Dr. Bartz: Glycoform ratio is dependent on very technical matters, what antibodies you use, what detection system you use. Those have to be standardized before you can start comparing from one lab to another.
Dr. Detwiler: The Japanese used a western blot they'd developed in their lab. It can't be compared across laboratories.
Dr. Bartz: That's problematic.
Accomplished this day, Wednesday, December 11, 2003, Denver, Colorado
The roundtable presentations and discussions were recorded. A transcript will be made availableto the Academy of Veterinary Consultants, theAmerican Association of Bovine Practitioners, and the Colleges of Veterinary Medicine throughout theUnited States and Canada. A condensed version translated for the livestock industry will be made available to educate livestock producers about prion related diseases.
http://www.r-calfusa.com/Newsletter/2004January.pdf
SEE FULL TEXT TME
http://transmissible-mink-encephalopathy.blogspot.com/
NOR-98 ATYPICAL SCRAPIE USA UPDATE AS AT OCT 2007
http://nor-98.blogspot.com/
USA BASE CASE, (ATYPICAL BSE), AND OR TSE (whatever they are calling it today), please note that both the ALABAMA COW, AND THE TEXAS COW, both were ''H-TYPE'', personal communication Detwiler et al Wednesday, August 22, 2007 11:52 PM. ...TSS
TEXAS AND ALABAMA MAD COW CASES
http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0703&L=sanet-mg&T=0&P=8125
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease inthe United States
http://cjdusa.blogspot.com/
TSS
posted by Terry S. Singeltary Sr. at
3:45 PM
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