Sunday, January 19, 2025

ON THE ORIGIN OF TME AND BSE, WHAT IF?

ON THE ORIGIN OF TME AND BSE, WHAT IF?

ON THE ORIGIN OF TRANSMISSIBLE MINK ENCEPHALOPATHY?

Slow Transmissible Diseases of the Nervous System: Volume

ON THE ORIGIN OF TRANSMISSIBLE MINK ENCEPHALOPATHY

R. F. Marsh and R. P. Hanson

Department of Veterinary Science, University of Wisconsin-Madison Madison, Wisconsin 53706

ABSTRACT Studies on mink susceptibility to sources of scrapie from the United States, but not from the United Kingdom, indicate that transmissible mink encephalopathy (TME) most likely originates from mink being fed scrapie-infected sheep or goat tissues. Experiments further suggest that the shortest natural route of infection is via bite wounds inflicted by littermates rather than by the oral route per se. Other studies, on the biologic characterization of the TIME agent from Sawyer County, Wisconsin, indicate that this particular source of TME is composed of a mixture of subpopulations which in- clude a hamster pathogen and a mink~monkey pathogen.

INTRODUCTION

In 1965, Hartsough and Burger reported a new disease of commercially reared mink which appeared to have a long incubation period based on epizootiologic observations on affected farms (1). These investigators were then successful in demonstrating that the disease was caused by a virus-like agent which produced a spongiform encephalopathy 6-9 months after experimental inoculation, the length of incubation being dependent on the route of exposure (2). This information in hand, it was immediately suggested that the new disease of mink was related to scrapie disease of sheep and goats.

Subsequent studies over the next five years extended the scrapie analogy in areas of agent characterization (3),

1These studies were supported by the College of Agri- cultural and Life Science, University of Wisconsin-Madison and by grants AI 11250 and NS 14822 from the National Institutes of Health,

R. F. Marsh and R. P, Hanson

pathogenesis (4), and host immune response (5). The disease was named transmissible mink encephalopathy (TME) by Marsh et al. (4) and this term now seems to be widely accepted, although it is still occasionally referred to as mink encephalopathy or encephalopathy of mink.

With so many disease features in common, it would seem a simple matter to demonstrate that TME results from feeding scrapie-infected tissues to mink. But such has not been the case, Epizootiologic studies of the 14 worldwide occurrences of TME have revealed probable exposure to scrapie in only one instance, a 1965 incidence in Finland in which the affected farm was the only one in the area feeding sheep heads (Kangas, personal communication). Experimentally, mink have been found to be susceptible to some sources of scrapie and the disease produced was in- distinguishable from TME (6). However, in these instances the incubation periods after intracerebral inoculation were one year or longer and do not seem to fulfill the criteria demanded by observation of natural occurrences of TME. Five of the 14 affected farms have experienced TME during or shortly after whelping season (May~June). In all of these cases the mortality rate has approached 100% of the adult animals, including first-year breeders not more than one year of age. Since TME is not con- genitally transmitted, we must conclude that the incubation periods in these instances were one year or less after oral exposure, a route requiring a longer incubation period than intracerebral inoculation.

The purpose of these present studies was to attempt to explain differences between field and experimental observations, and to further characterize the biologic Properties of the Sawyer County, Wisconsin, isolate of TME. Our results indicate that mink are more susceptible to sources of scrapie present in the United States than those found in the United Kingdom, and that bite wounds from littermates may represent a significant route of natural exposure. We further report that the TME source from Sawyer County can be separated into two components, a hamster pathogen and a mink-monkey pathogen,

MATERIALS AND METHODS

TME Agent. Originally recovered from a natural occurrence of TME on a Sawyer County, Wisconsin, mink farm in 1963 (2). The agent was passaged twice in mink before adaptation to hamsters (7).

Scrapie Agents. Various subpopulations of scrapie

On the Origin of Transmissible Mink Encephalopathy

agents, and their sheep or goat sources, were obtained from Dr. Alan Dickinson, A.R.C. Animal Breeding Research Organization, Edinburgh, Scotland. These agents were originally recovered from scrapie-affected animals in the United Kingdom, then separated into individual subpopulations by their biologic behavior in inbred strains of mice (8). We thank Dr. Dickinson for kindly supplying this material.

Additional sources of scrapie were obtained from the USDA Scrapie Field Trial in Mission, Texas. These inclued B-834, a naturally infected Nubian X Toggenburg goat; B-957, a Nubian X goat inoculated intracerebrally with brain from a scrapie-affected Suffolk sheep; and PR-81, a Suffolk sheep inoculated similarly to B-957. We thank Drs. Hourrigan, Klingsporn, and Clark for their cooperation and continuing interest in this work.

Inoculation.

All inocula were 5% or 10% brain suspensions in saline. Intracerebral inoculations on mink and squirrel monkeys were performed using an electric drill to perforate the calvarium, then the inoculum (0.1 ml or 0.2 ml, respectively) was injected into the right cerebral hemisphere using a 22 g needle.

RESULTS

UK Scrapie. The response of 16-month old mink to intracerebral inoculation with various sources of scrapie from the United Kingdom is shown in Table 1. Only one animal developed a progressive neurologic disease during an observation period of three years. This female sapphire mink had been injected with brain tissue from the scrapie- affected Suffolk sheep from which the subpopulation 138A was isolated. Histopathologic examination revealed an absence of spongiform degeneration in the brain of this mink, but widespread astrocytic hypertrophy in the frontal âcortex, striatum, thalamus, and hippocampus. These lesions were considered to be indicative of a TME-like disease process, especially since mink of this genotype (homozygous Aleutian) show very little endstage microvacuolation when affected with TME after two years of age (9). To further examine this finding, mink of varying ages and genotypes were inoculated intracerebrally with a 10% brain suspension from this animal. Incubation periods on second passage reduced to 9-10 months, and mink heterozygous for the Aleutian gene had severe spongiform degeneration in the cerebral hemispheres.

R. F. Marsh and R. P. Hanson

Table l, Susceptibility of mink to 5% or 10% brain suspen- sions from various subpopulations of scrapie or their sheep or goat sources in the United Kingdom.

INOCULUM RESPONSE* SSBP/1 0/3 22A 0/4 22C 0/4 Sheep Source 0/4 87A 0/2 87V 0/3 Sheep Source (RLE) 0/3 Sheep Source 0/2 51c 0/3 Sheep Source 1/2 (22 months) 138A 0/4 Sheep Source 0/3 104A 0/2 ME7 (Q) 0/2 Drowsy Goat 0/4 79A 0/3 79V 0/3 58A 0/3 Chandler 0/3 ME7 (J) 0/4 125A 0/4

*Number of mink developing TME-like disease within three years after intracerebral inoculation/number inoculated (incubation period in parentheses),

American Scrapie. The susceptibility of 12-month old mink to three sources of American scrapie administered by various routes of inoculation is shown in Table 2. B-834 was the most pathogenic source of scrapie for mink injected intracerebrally, producing incubation periods of 11-12 months. This Nubian X Toggenburg buck was naturally infected

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On the Origin of Transmissible Mink Encephalopathy

Table 2. Mink susceptibility to 10% brain suspensions from three sources of American scrapie.

INOCULUM ROUTE* RESPONSE** IC 6/6 (11-12 months) B-834 IM 5/5 (17-22months) per os 0/5 Ic 5/5 (18-24 months) B-957 IM 0/5 per os 0/5 Ic 5/5 (16-24 months) PR-81 IM 0/5 per os 0/5

*Mink injected with either 0.1 ml intracerebrally (IC), 0.5 ml intramuscularly (IM), or 3,0 ml per os using an oral dosing needle.

**Number of mink developing a TME-like disease within two years/number inoculated (range of incubation periods in parentheses).

via exposure to scrapie-contaminated pasture at Mission, Texas; the pasture being previously occupied by a flock of scrapie-affected Suffolk sheep. At 6 months of age, animal B-834 was removed from exposure and placed in a pen where he subsequently developed signs of scrapie at 40 months of age.

Mink inoculated with B~834 brain exhibited a typical clinical course of TME from behavioral changes, wasting and roughened fur, to progressive incoordination, somnolence and total debilitation. Neuropathologic lesions were indistinguishable from those seen in TME and included extensive microvacuolation in the cerebral hemispheres accompanied by reactive astrocytic hypertrophy. Lesions were bilaterally Symmetrical and limited entirely to gray matter.

Both B-957 and PR-81 produced TME-like disease in mink after incubation periods of up to 2 years. However, there was a marked difference in the distribution of lesions as compared to TME or B-834. The microvacuolation and astrocytic hypertrophy were not limited to the gray matter, but could be found with equal intensity in both white and gray matter in the cerebral hemispheres as well as in brain stem, cerebellum and spinal cord.

Ten per cent brain suspensions from B-834, and from two mink developing TME-like disease after inoculation with B-834, were injected intracerebrally into weanling,

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R. F. Marsh and R. P. Hanson

random-bred white mice. Mice inoculated with B-834 brain developed scrapie after 12 months, Mice inoculated with either of the mink brain suspensions remained unaffected for their lifespan of approximately 24 months.

Hamster-adapted TME. In an attempt to study the effects of host modification on species susceptibility, hamster-adapted TME brain was backpassaged into mink after both the third (10/10 LD50/gram of brain tissue) and sixth (10/9.3 LD50/gram of brain tissue) hamster passage. Results are summarized in Table 3.

Table 3. Effect of hamster-adaptation on mink susceptibility to TME.

PASSAGE INCUBATION* TITER** 3rd 26 weeks 6.8 6th 58 weeks 2.0

*Length of incubation period after intracerebral inoculation with 10% brain suspensions. **Log10LD50/gram of brain tissue as calculated by the Spearman-Karber method after titration in mink.

Brain suspensions from mink affected with TME after injection with third passage hamster-adapted TME were inoculated back into seven hamsters intracerebrally, These animals appeared normal for a period of 18 months at which time three developed a TME-like disease while four remained unaffected for their remaining lifespan.

A similar experiment to the above was performed in squirrel monkeys in which two animals were each inoculated intracerebrally with third passage hamster~adapted TME. These animals developed TME-like disease in 55 and 60 weeks. Hamster backpassage of brain material from one of these monkeys resulted in an incubation period of 44 weeks in hamsters inoculated with a 10% brain suspension and an endpoint titer of 10/3LD50/gram of brain tissue.

DISCUSSION AND ADDITIONAL RESULTS

Sources of scrapie from the United Kingdom had little mink pathogenicity whether tested as individual subpopulations or from their sheep or goat origins. Conversely, American scrapie, both in this study and in others (6), is

On the Origin of Transmissible Mink Encephalopathy

consistently pathogenic for mink, although relative susceptibility varies depending on the source of inoculum. Since we do not as yet fully understand all factors influencing species susceptibility, one can only speculate as to the reasons for this difference. Almost all of the scrapie in the United States occurs in the Suffolk breed of sheep. An obvious explanation would be that this breed potentiates the disease for carnivores, either by host modification or selection of subpopulations.

These are the first studies to compare sheep and goat scrapie in mink. Although goat B-834 did produce incuba- tion periods of only 11-12 months, it is apparent that this increased pathogenicity is not due to a goat effect alone since both B-957 and PR-81 produced similar responses in mink. Furthermore, the different distribution of lesions produced by these later two inocula show that scrapie can have different pathologic expressions in mink than typically recognized as TME. Therefore, it should be expected that the pathology of natural TME will vary depending on the source of scrapie to which mink are exposed. Johannsen and Hartung have reported an incidence of TME occurring in East Germany in 1967 in which affected mink had diffuse cerebral "edema" and widespread lesions in the spinal cord (10).

Even though B-834 produced short incubation periods when inoculated intracerebrally, exposure by the oral route was ineffective during an observation period of two years. Thus, we once again seem to have a conflict between field and experimental data. However, Gajdusek has suggested that the main route of entry for these transmissible agents is not the oral route per se, but rather via breaks or abrasions of skin and mucosal surfaces (11). To examine this possibility, we tested third mink passage TME brain for neuro-invasiveness after intra-

Table 4. Comparison of infectivity of a 10% TME mink brain suspension tested by intracerebral (IC), intramuscular (1M), or intradermal (ID) inoculation.

INOCULATION RESPONSE**

Ic (0.1 ml, right cerebral hemisphere) 5/5 (20-23 weeks)

IM (0.5 ml, right hind leg) 5/5 (24-30 weeks)

ID (0.05 ml, right foreleg) 17/17 (24-40 weeks)

*Number of mink developing TME/number inoculated, excluding intercurrent deaths (range of incubation periods in parentheses),

R. F. Marsh and R. P. Hanson

dermal inoculation. The results are presented in Table 4.

The intradermal route appears to be an efficient means of exposure and one with a high potential for occurrence, considering mink husbandry practices. Mink kits are born in May and kept together as litters until August. During this period there is considerable fighting among littermates, especially at feeding time. It is easy to imagine how the scrapie agent could be introduced through bite wounds from feeding animals; each tooth a tiny inoculation needle. If this scenario is correct, the devastating occurrences of TME seen in the spring have not happened by chance, but are the result of mink being exposed to scrapie the previous summer, before separation into individual cages.

We have previously mentioned factors influencing species susceptibility to these transmissible agents, Terms such as "genetic predisposition", "host modification", and "selection of subpopulations" are freely used, but poorly understood. These experiments have shown once again that mouse pathogenicity of scrapie is markedly reduced after only a single passage in mink. This appears to be the best example yet for a possible host modification effect on scrapie agent. Such a dramatic change in host range could be explained by modification of a viral component after replication in a heterologous system. Perhaps, there is a critical host-contributed component to scrapie agent which modulates infectivity of susceptible cells.

However, while the effects of host modification remain questionable, there is a growing body of evidence to indicate that host selection of subpopulations of scrapie is an important mechanism by which these agents adapt to different populations of animals. Kimberlin and Walker, studying hamster-adapted scrapie, have been able to Separate out two distinct populations, each with different host pathogenicities (12). A similar mechanism may explain our results with interspecies passage of hamster~adapted TME. The decrease in hamster pathogenicity after passage in mink or squirrel monkeys may indicate that the TME inoculum is composed of a mixture of agents and that passage in different hosts potentiates different subpopulations (Figure 1). This explanation becomes more attractive in light of evidence that hamster-adapted scrapie loses none of its pathogenicity for hamsters after passage in squirrel monkeys (R.F. Marsh, unpublished). This would argue against host modification since squirrel monkeys represent a common species which would be expected to alter both disease agents similarly.

To test this possibility we attempted to separate out the

On the Origin of Transmissible Mink Encephalopathy

hamster pathogen by two serial hamster Passages of hamster- adapted TME at high dilution (10-7). Hamster brain from the second serial passage was then inoculated as a 20% suspension into both mink and squirrel monkeys. Both of these species, which previously developed TME within 60 weeks after inoculation with unseparated hamster-adapted TME, remain unaffected after 108 weeks. These results, in combination with our previous studies showing that monkey~passaged TME retains a high mink LD50 endpoint, indicate that the Sawyer County source of TME is composed of a mixture of at least two subpopulations, a hamster pathogen and a mink-monkey pathogen. We would like to emphasize, however, that we do not consider these host restrictions to be absolute, nor that they infer a consistent relationship from one source of scrapie to another. In this particular instance, the mink and monkey pathogen appear to be one and the same, but other results (R.F. Marsh, unpublished) clearly show that different sources of Scrapie vary in their mink and monkey pathogenicities and that, therefore, these host specificities segregate independent of one another.

FIGURE 1. Diagrammatic illustration of mixture of a hamster pathogen (H) and mink-monkey (M) pathogen in the Sawyer County source of TME, and enrichment of subpopulations after animal passage.

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R. F. Marsh and R. P. Hanson

In summary, our studies have shown a difference in mink pathogenicity of scrapie sources from the United Kingdom as compared to the United States. They also offer a reasonable explanation for differences observed between field incidences of TME and experimental studies on mink susceptibility to scrapie. Therefore, there appear to be no major obstacles remaining to the probable fact that TME originates from feeding mink scrapie~infected tissues, a conclusion Dr. Eklund reached many years ago.

REFERENCES

Hartsough, G. R., and Burger, D. (1965). J. Infect. Dis., 115, 387.

Burger, D., and Hartsough, G. R. (1965). J. Infect. Dis., 115, 393.

Marsh, R. F., and Hanson, R. P. (1969). J. Virol., 3, 176.

Marsh, R. F., Burger, D., and Hanson, R. P. (1969). Am. J. Vet. Res., 30, 1937.

Marsh, R. F., Pan, I. C., and Hanson, R. P. (1970). Infect. Immun., 7, 352.

Hanson, R. P., Eckroade, R. J., Marsh, R. P., Zu Rhein, G. M., Kanitz, C. L., and Gustafson, D. P. (1971), Science, 172, 859.

Marsh, R. F., Burger, D., Eckroade, R. J., Zu Rhein, G. M., and Hanson, R. P. (1969). J. Infect. Dis., 120, 713.

Dickinson, A. G. (1976). In "Slow Virus Diseases of Animals and Man" (R, H. Kimberlin, ed.), pp. 209-241.

Elsevier, Amsterdam.

Marsh, R. F., Sipe, J. C., Morse, S. S., and Hanson, R. P. (1976). Lab. Invest., 34, 381.

Johannsen, U., and Hartung, J. (1970). Monatsh. Vet. Med., 25, 389.

Gajdusek, D. C. (1977). Science, 197, 943. Kimberlin, R. H., and Walker, C. A. (1978). J. Gen. Virol., 39, 487.

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But, history showed;

1985

Evidence That Transmissible Mink Encephalopathy Results from Feeding Infected Cattle Over the next 8-10 weeks, approximately 40% of all the adult mink on the farm died from TME.

snip...

The rancher was a ''dead stock'' feeder using mostly (>95%) downer or dead dairy cattle...

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https://web.archive.org/web/20090506024922/http://www.bseinquiry.gov.uk/files/yb/1987/06/10004001.pdf

years later Marsh finds out;

Part of the Proceedings of an International Roundtable on Bovine Spongiform Encephalopathy, Bethesda, Maryland, USA, June 27-28, 1989.

The possibility of infection with BSE in the United States, as defined by studies on the disease in Great Britain, is judged to be low on the basis of the following: (1) meat and bonemeals imported into the United States from Great Britain between 1980 and 1988 were used mainly in poultry, not ruminant feed; (2) the Scrapie Eradication Program had reduced the prevalence of scrapie in the United States compared with that in Great Britain; and (3) little, if any, rendered animal products are used for protein supplements in cattle feed in the United States. However, there is some evidence that there may already be a scrapie-like disease in cattle in the United States. This evidence comes from epidemiologic studies on an incident of transmissible mink encephalopathy (TME) in Stetsonville, Wis, in 1985. This mink farmer used no commercially available animal by-product mixtures in his feed, but instead slaughtered all animals going into the mink diet, which included mostly (>95%) "downer" dairy cows, a few horses, but never sheep. To examine the possibility that cattle may have been the source of this incident of TME, two 6-week-old Holstein bull calves were inoculated intracerebrally with mink brain from the affected farm. The bulls developed neurologic disease 18 and 19 months after inoculation. Both brains had spongiform degeneration at necropsy and both were transmissible back to mink by either intracerebral (incubation period of 4 months) or oral (incubation period of 7 months) inoculation Whereas TME has been thought to be caused by feeding scrapie-infected sheep to mink, this theory has no conclusive evidence. Experimental oral inoculation of mink with several different sources of sheep scrapie has never been successful, and an incubation period of less than 12 months has never (sic) produced by intracerebral inoculation. Transmissible mink encephalopathy can develop naturally by infection with incubation periods of less than 12 months. There is reason to believe that scrapie has not been transmitted in the United States from sheep to cattle by rendered protein concentrates as it was in Great Britain. However, some circumstantial evidence exists that cattle may be a source of some TME infections. It is recommended that we increase our surveillance for a BSE-like disease in American cattle by encouraging state diagnostic laboratories to formalin-fix specimens of midbrain and brain stem from bovine brains submitted for rabies testing. If results of these tests are negative, these fixed tissues can then be examined for evidence of spongiform degeneration of the gray matter.

Letter to the Editor, Journal of the American Veterinary Medical Association, August 15, 1990 In my article, "Bovine spongiform encephalopathy in the United States" (JAVMA, May 15, 1990, p 1677), I stated that "little, if any, rendered animal products are used for protein supplements in cattle feed in the United States." I have since learned that this is incorrect, because of the recent trend of using less assimilated "by-pass" proteins in cattle feed. A large amount of meat-and-bone meal is being fed to American cattle, and this change in feeding practice has greatly increased the risk of bovine spongiform encephalopathy (BSE) developing in the United States. Epidemiologic studies on BSE in Great Britain have indicated that the disease originated in cattle by exposure to the heat-resistant transmissible agent in compounded feed containing rendered animal protein. The most likely source of infection was assumed to be meat-and-bone meal prepared from scrapie-infected sheep, but it is also possible that a heretofore unrecognized scrapie-like infection of cattle could have been spread in the same manner. Because of concern for the possible development of BSE in the United States, the American rendering industry discontinued the processing of fallen and sick sheep last December. In my opinion, this was a prudent policy, but one that will not prevent the possible transmission of BSE from cattle to cattle. As emphasized in my article, there is some evidence that BSE-like infection may already exist in American cattle. The current practice of feeding meat-and-bone meal to cattle solidifies the most important means to perpetuate and amplify the disease cycle. In Great Britain, BSE has produced a great economic and emotional burden. We must take all reasonable measures to prevent BSE from developing in the United States. Therefore, the practice of using animal protein in cattle feed should be discontinued as soon as possible. Waiting until the first case of BSE is diagnosed in the United States will certainly be "closing the barn door after the horse is gone." With a disease having a 3- to 6-year incubation period, thousands of animals would be exposed before we recognize the problem and, if that happens, we would be in for a decade of turmoil. R. F. Marsh, DVM, PhD Madison, Wis

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

ABSTRACT 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.

INTRODUCTION

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 in scrapie-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.

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 formal 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 somnolence in 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 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.

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 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 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 if this proposed epidemiologic association is to be confirmed.

ACKNOWLEDGEMENTS 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.

REFERENCES Burger, D. and Hartsough, G.R. 1965. Encephalopathy of mink. II. Experimental and natural 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 and clinical observations. 3. Infec. Dis. 115:387-392. Marsh, R.F. and Hanson, R.P. 1969. Physical and chemical properties of the transmissible mink encephalopathy agent. 3. ViroL 3:176-180. Marsh, R.F. and Hanson, R.P. 1979. On the origin of transmissible mink encephalopathy. In Hadlow, W.J. and Prusiner, S.P. (eds.) Slow transmissible diseases 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 in cattle? Proceedings of the Seventh Annual Western Conference for Food Animal Veterinary 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 spongiform encephalopathy in cattle. Vet. Rec. 121:419-420.

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On The Origin Of BSE, What If?

Bovine Spongiform Encephalopathy BSE TSE Prion Origin USA?, what if?

Research Project: Pathobiology, Genetics, and Detection of Transmissible Spongiform Encephalopathies Location: Virus and Prion Research

Title: Sheep are susceptible to the agent of TME by intracranial inoculation and have evidence of infectivity in lymphoid tissues

Author item CASSMANN, ERIC - Oak Ridge Institute For Science And Education (ORISE) item MOORE, SARA - Oak Ridge Institute For Science And Education (ORISE) item SMITH, JODI - Iowa State University item Greenlee, Justin

Submitted to: Frontiers in Veterinary Science Publication Type: Peer Reviewed Journal Publication Acceptance Date: 11/14/2019 Publication Date: 11/29/2019 Citation: Cassmann, E.D., Moore, S.J., Smith, J.D., Greenlee, J.J. 2019.

Sheep are susceptible to the agent of TME by intracranial inoculation and have evidence of infectivity in lymphoid tissues.

Frontiers in Veterinary Science. 6:430. https://doi.org/10.3389/fvets.2019.00430. DOI: https://doi.org/10.3389/fvets.2019.00430

Interpretive Summary: Prion diseases are protein misfolding diseases that are transmissible between animals. The outcome of prion infection is irreversible brain damage and death. Transmission can occur between animals of the same or different species, however, transmission between different species is usually less efficient due to the species barrier, which results from differences in the amino acid sequence of the prion protein between the donor and recipient species. The present work evaluated whether transmissible mink encephalopathy (TME) can infect sheep. Our results demonstrate that sheep are susceptible to the TME agent and that the TME agent has similar properties to the agent of L-type atypical bovine spongiform encephalopathy (L-BSE). This work supports the ideas that L-BSE is a possible source for TME in mink and that the practice of feeding cattle with neurologic disease to mink should be avoided. This information is important to farmers who raise cattle, sheep, or mink.

Technical Abstract: Transmissible mink encephalopathy (TME) is a food borne prion disease. Epidemiological and experimental evidence suggests similarities between the agent of TME and L-BSE. This experiment demonstrates the susceptibility of four different genotypes of sheep to the agent of TME by intracranial inoculation. The four genotypes of sheep used in this experiment had polymorphisms corresponding to codons 136 and 171 of the prion gene: VV136QQ171, AV136QQ171, AA136QQ171, and AA136QR171. All intracranially inoculated sheep without comorbidities (15/15) developed clinical scrapie and had detectable PrPSc by immunohistochemistry, western blot, and enzyme immunoassay (EIA). The mean incubation periods in TME infected sheep correlated with their relative genotypic susceptibility. There was peripheral distribution of PrPSc in the trigeminal ganglion and neuromuscular spindles; however, unlike classical scrapie and C-BSE in sheep, ovine TME did not accumulate in the lymphoid tissue. To rule out the presence of infectious, but proteinase K susceptible PrPSc, the lymph nodes of two sheep genotypes, VV136QQ171 and AA136QQ171, were bioassayed in transgenic ovinized mice. None of the mice (0/32) inoculated by the intraperitoneal route had detectable PrPSc by EIA. Interestingly, mice intracranially inoculated with RPLN tissue from a VV136QQ171 sheep were EIA positive (3/17) indicating that sheep inoculated with TME harbor infectivity in their lymph nodes. Western blot analysis demonstrated similarities in the migration patterns between ovine TME and the bovine TME inoculum. Overall, these results demonstrate that sheep are susceptible to the agent of TME, and that the tissue distribution of PrPSc in TME infected sheep is distinct from classical scrapie.

https://www.ars.usda.gov/research/publications/publication/?seqNo115=363305

https://www.ars.usda.gov/research/publications/publication/?seqNo115=360665

https://www.ars.usda.gov/research/publications/publication/?seqNo115=373668

Previous work has shown that the Stetsonville, WI outbreak of TME could have been precipitated by feeding mink a downer cow with atypical BSE; therefore, it very well may have originated from a cow with L-BSE. The agent of TME appears to remain stable, and it has a high transmission efficiency after a sequence of interspecies transmission events. Although C-BSE is the archetypal foodborne TSE, our findings indicate that L-BSE and bTME have greater transmission efficiencies in bovinized mice. Previous work has demonstrated that L-BSE also is more virulent than C-BSE in mice expressing the human prion protein [46, 55]. Although the documented incidence of L-BSE is low, the propensity of L-BSE and the TME agent to cross species barriers support the continued monitoring for atypical BSE.

https://bmcvetres.biomedcentral.com/articles/10.1186/s12917-020-02611-0

***>This work supports the ideas that L-BSE is a possible source for TME in mink and that the practice of feeding cattle with neurologic disease to mink should be avoided. This information is important to farmers who raise cattle, sheep, or mink.<***

NOW, BE AWARE, OIE AND USDA HAVE NOW MADE ATYPICAL SCRAPIE AND ATYPICAL BSE A LEGAL TRADING COMMODITY, WITH NO REPORTING OF SAID ATYPICAL CASES, EXCEPT FOR A VOLUNTARY NOTE ON ANNUAL REPORT...i don't make this stuff up...terry

USA testing <25K cattle annually for BSE, BUT, even at those low testing figures, the USA did just confirm another case of BSE just here recently. Feed ban has failed terribly, and CWD is spreading in the USA, at an alarming rate. Recent transmission studies show oral transmission of CWD of Cervid to cattle. Studies also show links of sporadic CJD to BSE, Scrapie, and CWD. It’s a Whole new game of Prion poker now$$$

Wednesday, May 24, 2023

***> WAHIS, WOAH, OIE, United States of America Bovine spongiform encephalopathy Immediate notification

https://wahis.woah.org/#/in-review/5067

https://woahoie.blogspot.com/2023/05/wahis-woah-oie-united-states-of-america.html

https://prpsc.proboards.com/thread/125/wahis-woah-oie-immediate-notification

SATURDAY, MAY 20, 2023

***> Tennessee State Veterinarian Alerts Cattle Owners to Disease Detection Mad Cow atypical L-Type BSE

https://bse-atypical.blogspot.com/2023/05/tennessee-state-veterinarian-alerts.html

https://prpsc.proboards.com/thread/123/tennessee-veterinarian-alerts-cattle-confirmed

MAY 19, 2023

https://www.aphis.usda.gov/aphis/newsroom/stakeholder-info/sa_by_date/sa-2023/bse

2 weeks before the announcement of this recent mad cow case in the USA, i submitted this to the APHIS et al;

***> APPRX. 2 weeks before the recent mad cow case was confirmed in the USA, in Tennessee, atypical L-Type BSE, I submitted this to the APHIS et al;

Document APHIS-2023-0027-0001 BSE Singeltary Comment Submission May 2, 2023

''said 'burden' cost, will be a heavy burden to bear, if we fail with Bovine Spongiform Encephalopathy BSE TSE Prion disease, that is why this information collection is so critical''...

https://www.regulations.gov/comment/APHIS-2023-0027-0002

https://downloads.regulations.gov/APHIS-2023-0027-0002/attachment_1.pdf

SUNDAY, JANUARY 19, 2025 

Scrapie Field Trial was developed at Mission, Texas, what if? 


USAHA 128th Meeting Resolution CWD and Scrapie Unfortunately, since 2019, federal support for the scrapie program has eroded, particularly regarding the individual animal identification and surveillance components of the program.


Terry S. Singeltary Sr
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