Saturday, December 01, 2007

Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse Model

Volume 13, Number 12–December 2007

Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-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


Transmissible mink encepholapathy (TME) is a foodborne transmissible spongiform encephalopathy (TSE) of ranch-raised mink; infection with a ruminant TSE has been proposed as the cause, but the precise origin of TME is unknown. To compare the phenotypes of each TSE, bovine-passaged TME isolate and 3 distinct natural bovine spongiform encephalopathy (BSE) agents (typical BSE, H-type BSE, and L-type BSE) were inoculated into an ovine transgenic mouse line (TgOvPrP4). Transgenic mice were susceptible to infection with bovine-passaged TME, typical BSE, and L-type BSE but not to H-type BSE. Based on survival periods, brain lesions profiles, disease-associated prion protein brain distribution, and biochemical properties of protease-resistant prion protein, typical BSE had a distint phenotype in ovine transgenic mice compared to L-type BSE and bovine TME.The similar phenotypic properties of L-type BSE and bovine TME in TgOvPrP4 mice suggest that L-type BSE is a much more likely candidate for the origin of TME than is typical BSE.



These studies provide experimental evidence that the Stetsonville TME agent is distinct from typical BSE but has phenotypic similarities to L-type BSE in TgOvPrP4 mice. Our conclusion is that L-type BSE is a more likely candidate for a bovine source of TME infection than typical BSE. In the scenario that a ruminant TSE is the source for TME infection in mink, this would be a second example of transmission of a TSE from ruminants to non-ruminants under natural conditions or farming practices in addition to transmission 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 mice and macaques, suggests that L-type BSE is more pathogenic for humans than typical BSE (24,38).

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


The general opinion of those present was that BSE, as an overt disease phenomenon, _could exist in the USA, but if it did, it was very rare. The need for improved and specific surveillance methods to detect it as recognised...


It is clear that USDA have little information and _no_ regulatory responsibility for rendering plants in the US...


3. Prof. A. Robertson gave a brief account of BSE. The US approach was to accord it a _very low profile indeed_. Dr. A Thiermann showed the picture in the ''Independent'' with cattle being incinerated and thought this was a fanatical incident to be _avoided_ in the US _at all costs_...


please read this old full text document !

To be published in the Proceedings of the Fourth International Scientific Congress in Fur Animal Production. Toronto, Canada, August 21-28, 1988

Evidence That Transmissible Mink Encephalopathy Results 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, Wisconsin 53092


Epidemiologic investigation of a new incidence of transmissible mink encephalopathy (TME) in Stetsonville, Wisconsin suggests that the disease may have resulted from feeding infected cattle to mink. This observation is supported by the transmission of a TME-like disease to experimentally inoculated cattle, and by the recent report of a new bovine spongiform encephalopathy in England.


Transmissible mink encephalopathy (TME) was first reported in 1965 by Hartsough and Burger who demonstrated that the disease was transmissible with a long incubation period, and that affected mink had a spongiform encephalopathy similar to that found inscrapie-affecied sheep (Hartsough and Burger, 1965; Burger and Hartsough, 1965). Because of the similarity between TME and scrapie, and the subsequent finding that the two transmissible agents were indistinguishable (Marsh and Hanson, 1969), it was concluded that TME most likely resulted from feeding mink scrapie-infecied sheep. The experimental transmission of sheep scrapie to mink (Hanson et al., 1971)confirmed the close association of TME and scrapie, but at the same time provided evidence that they may be different. Epidemiologic studies on previous incidences of TME indicated that the incubation periods in field cases were between six months and one year in length (Harxsough and Burger, 1965). Experimentally, scrapie could not be transmitted to mink in less than one year.To investigate the possibility that TME may be caused by a (particular strain of scrapie which might be highly pathogenic for mink, 21 different strains of the scrapie agent, including their sheep or goat sources, were inoculated into a total of 61 mink. Only one mink developed a progressive neurologic disease after an incubation period of 22 mon..s (Marsh and Hanson, 1979). These results indicated that TME was either caused by a strain of sheep scrapie not yet tested, or was due to exposure to a scrapie-like agent from an unidentified source.


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 a single area, hyperexcitability, difficulty in chewing and swallowing, and tails arched over their backs like squirrels. These signs were followed by progressive deterioration of neurologic 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 12-18months. 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 by histopaihologic examination and by experimental transmission to mink after incubation periods of four months. To investigate the possible involvement of cattle in this disease cycle, two six-week old castrated Holstein bull calves were inoculated intracerebrally with a brain suspension from affected mink. Each developed a fatal spongiform encephalopathy after incubation periods of 18 and 19 months.


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 possible relationship to scrapie. Because this new bovine disease in England is characterized by behavioral changes, hyperexcitability, and agressiveness, it is very likely it would be confused 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 with anti-rabies virus antibody and are not examined histopathologically for lesions of spongiform 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 back passage 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-adapted TME agents (Marsh and Hanson, 1979). The intracerebral back passage 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 if this proposed epidemiologic association is to be confirmed.


These studies were supported by the College of Agricultural and Life Sciences, University of Wisconsin-Madison and by a grant (85-CRCR-1-1812) from the United States Department of Agriculture. The authors also wish to acknowledge the help and encouragement of Robert Hanson who died during the course of these investigations.


Burger, D. and Hartsough, G.R. 1965. Encephalopathy of mink. II. Experimental andnatural transmission. J. Infec. Dis. 115:393-399.Hanson, R.P., Eckroade, R.3., Marsh, R.F., ZuRhein, C.M., Kanitz, C.L. and Gustatson,D.P. 1971. Susceptibility of mink to sheep scrapie. Science 172:859-861.Hansough, G.R. and Burger, D. 1965. Encephalopathy of mink. I. Epizoociologic andclinical observations. 3. Infec. Dis. 115:387-392.Marsh, R.F. and Hanson, R.P. 1969. Physical and chemical properties of thetransmissible mink encephalopathy agent. 3. ViroL 3:176-180.Marsh, R.F. and Hanson, R.P. 1979. On the origin of transmissible minkencephalopathy. In Hadlow, W.J. and Prusiner, S.P. (eds.) Slow transmissiblediseases of the nervous system. Vol. 1, Academic Press, New York, pp 451-460.Marsh, R.F. and Hartsough, G.R. 1986. Is there a scrapie-like disease incattle? Proceedings of the Seventh Annual Western Conference for Food AnimalVeterinary Medicine. University of Arizona, pp 20.Wells, G.A.H., Scott, A.C., Johnson, C.T., Cunning, R.F., Hancock, R.D.,Jeffrey, M., Dawson, M. and Bradley, R. 1987. A novel progressive spongiformencephalopathy in cattle. Vet. Rec. 121:419-420.


In Confidence - Perceptions of unconventional slow virus diseasesof animals in the USA - APRIL-MAY 1989 - G A H Wells

Subject: TME hyper/drowsy, INTER-SPECIES TRANSMISSION CWD and strain
properties Date: October 22, 2007 at 12:48 pm PST

Completely Edited Version


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, what ever strain is produced is probably going to be the predominant one because it has a jump start 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 these effects. 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 of strains 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 host range. 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 becareful 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 hostPRPSC? 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 incubation period. 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 available to the Academy of Veterinary Consultants, the American Association of Bovine Practitioners, and the Colleges of Veterinary Medicine throughout the United States and Canada. A condensed version translated for the livestock industry will be made available to educate livestock producers about prion related diseases.





Date: Mon, 24 Sep 2007 21:31:55 -0500

I suggest that you all read the data out about h-BASE and sporadic CJD, GSS, blood, and some of the other abstracts from the PRION2007. ...


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

see full text 143 pages ;

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