Scientific papers on Spongiform Disease by R.F. Marsh

Experimental infection of cattle with the agents of transmissible mink encephalopathy and scrapie.

 J Comp Pathol 113 (3): 241-251 (1995) 
 Robinson MM, Hadlow WJ, Knowles DP, Huff TP, Lacy PA, Marsh RF, Gorham JR
 USDA-ARS Animal Disease Research Unit, Washington State University, Pullman 99164-7030, USA.

Cattle are susceptible to experimental infection with the Stetsonville isolate of the transmissible mink encephalopathy (TME) agent. To determine if they are susceptible to other TME isolates, two groups of calves were inoculated intracerebrally with homogenate of mink brain containing the Hayward isolate or the Blackfoot isolate. For comparison, a third group was inoculated with a brain homogenate from a steer infected with the Stetsonville isolate in its primary cattle passage and a fourth group was inoculated with a pool of brain homogenate from three cattle experimentally infected with a sheep and goat scrapie agent in its primary cattle passage. Clinical signs of neurological disease appeared in each steer of every group between 15 and 25 months after inoculation. An encephalopathy characterized by severe spongiform change and pronounced astrocytosis occurred in the three groups inoculated with the TME agent. In contrast, the neurohistological changes in the steers inoculated with the cattle-passaged scrapie agent were slight and subtle. Analysis of the octapeptide repeat region of the bovine protease-resistant protein (PrP) gene showed that variations in incubation period, clinical signs, and neurohistological changes were unrelated to the homozygous or heterozygous condition of six or six/five octapeptide repeats.

Experimental infection of mink with bovine spongiform encephalopathy.

J Gen Virol 75 ( Pt 9): 2151-2155 (1994) 
 Robinson MM, Hadlow WJ, Huff TP, Wells GA, Dawson M, Marsh RF, Gorham JR
 USDA-ARS Animal Disease Research Unit, Pullman, Washington 99164-7030. 

To determine whether the aetiological agent of bovine spongiform encephalopathy (BSE) is pathogenic for mink, standard dark mink were inoculated with coded homogenates of bovine brain from the U.K. Two homogenates were from cows affected with BSE. The third was from a cow that came from a farm with no history of having had BSE or having been fed ruminant-derived, rendered by-products, the proposed vehicle for introduction of the BSE agent. Each homogenate was inoculated intracerebrally into separate groups of mink and a pool of the three was fed to a fourth group. Signs of neurological disease appeared in mink an average of 12 months after intracerebral inoculation and 15 months after feeding. Decreased appetite, lethargy and mild to moderate pelvic limb ataxia were the predominant clinical signs, quite unlike the classic clinical picture of transmissible mink encephalopathy (TME). Microscopic changes in brain sections of most affected mink were those of a scrapie-like spongiform encephalopathy. Vacuolar change in grey matter neuropil was accompanied by prominent astrocytosis. Varying greatly in severity from one mink to another, the degenerative changes occurred in the cerebral cortex, dorsolateral gyri of the frontal lobe, corpus striatum, diencephalon and brainstem. Although resembling TME, the encephalopathy was distinguishable from it by less extensive changes in the cerebral cortex, by more severe changes in the caudal brainstem and by sparing of the hippocampus. The results of this study extend the experimental host range of the BSE agent and demonstrate for the first time the experimental oral infection of mink with a transmissible spongiform encephalopathy agent from a naturally infected ruminant species.

Philos Trans R Soc Lond B Biol Sci 343 (1306): 413-414 (1994) Physicochemical and biological characterizations of distinct strains of the transmissible mink encephalopathy agent. Marsh RF, Bessen RA Department of Animal Health and Biomedical Sciences, University of Wisconsin, Madison 53706. Inoculation of the Stetsonville, Wisconsin source of transmissible mink encephalopathy (TME) into Syrian hamsters has identified two strains of the TME agent having distinct biological properties and producing disease-specific prion proteins (PrPTME) having different physicochemical properties. Although several strains of the sheep scrapie agent have been identified in Great Britain, this is the first indication that agents producing transmissible spongiform encephalopathies in the United States also are capable of producing distinct strains.

Immunolocalization of scrapie amyloid in non-congophilic, non-birefringent deposits in golden Syrian hamsters with experimental transmissible mink encephalopathy.

 Neurosci Lett 155 (1): 112-115 (1993) 
 Guiroy DC, Marsh RF, Yanagihara R, Gajdusek DC
 Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke,
National Institute of Health, Bethesda, MD 20892. 

Transmissible mink encephalopathy (TME), a naturally occurring subacute spongiform encephalopathy in commercially ranch-reared mink (Mustela vision), is characterized neuropathologically by spongiform changes in the neuropil, intracytoplasmic neuronal vacuolation and astrocytic hypertrophy and hyperplasia. Amyloid deposits have not been observed in brain tissue sections from animals with natural and experimental TME using conventional histochemical stains such as Congo red. To determine if amyloid deposits be visualized by immunocytochemical techniques, we stained formalin-fixed, formic acid-treated brain tissue sections from several animal species with natural and experimental TME, using a rabbit antiserum directed against scrapie amyloid (PrP27-30). Scrapie amyloid-immunoreactive deposits were found in golden Syrian hamsters experimentally infected with TME, but were absent in mink with natural and experimental TME, as well as in ferrets and squirrel monkeys with experimental TME. The scrapie amyloid-immunoreactive deposits, which were non-congophilic and non-birefringent, were distributed in the subependymal, subpial and perivascular regions of the brain, as in hamsters infected with the 263K strain of scrapie. Ultrastructurally, scrapie amyloid-immunoreactive deposits revealed a collection of degenerating neurites with numerous abnormal mitochondria and degenerating synapses. Amyloid fibrils were not observed. Anti-scrapie amyloid antibodies immunoabsorbed with scrapie amyloid abolished immunostaining. Our data indicate the presence of scrapie amyloid lacking the molecular conformation of amyloid fibrils in hamsters with experimental TME.

Epidemiologic and experimental studies on transmissible mink encephalopathy.

Dev Biol Stand 80: 111-118 (1993) 
Marsh RF, Bessen RA
Department of Animal Health and Biomedical Sciences, University of Wisconsin-Madison 53706. 

Transmissible mink encephalopathy (TME) is a rare foodborne disease of ranch-raised mink produced by an as yet unidentified contaminated feed ingredient. Because of the clinicopathologic similarities to scrapie and the indistinguishable physicochemical properties of their transmissible agents, it was initially assumed that TME was caused by feeding mink scrapie-infected sheep. However, subsequent studies testing the oral susceptibility of mink to scrapie were unsuccessful. Epidemiologic investigations of individual incidents of TME have not identified an association between the occurrence of disease and the feeding of any particular ingredient. However, there are two incidents in which the rancher was confident that sheep were not fed. The most recent of these was in Stetsonville, Wisconsin in 1985 where the meat portion of the diet was composed almost exclusively of downer dairy cows. To examine the possibility that cattle may have been the source of infection on the Stetsonville ranch, mink brain was experimentally inoculated intracerebrally into two Holstein steers. Both of these animals developed fatal spongiform encephalopathies 18 and 19 months after inoculation. These findings are compatible with the Stetsonville incident of TME being caused by feeding mink infected cattle tissue and they suggest the presence of an unrecognized BSE-like disease in the United States. Further experimental studies on the Stetsonville source of TME have identified two distinct strains of the transmissible agent in Syrian hamsters. These strains vary in length of incubation period, clinical signs, endstage brain infectivity titre, and pathogenicity for mink.

Bovine spongiform encephalopathy: a new disease of cattle?

Arch Virol Suppl 7: 255-259 (1993) 
Marsh RF
Department of Animal Health and Biomedical Sciences, University of Wisconsin-Madison. 

Bovine spongiform encephalopathy (BSE) was first recognized in Great Britain in 1985. Most believe that the disease is of recent origin initiated by feeding rendered animal protein from scrapie-infected sheep to cattle, then perpetuated by feeding rendered infected cattle to other cattle. This paper explores an alternative hypothesis that BSE existed in cattle populations in an unrecognized form for a much longer time until amplified by changes in the rendering process that allowed cattle to cattle transmission to occur. This viewpoint is supported by observations that transmissible mink encephalopathy, a disease that first occurred 45 years ago, is likely caused by feeding downer cows to mink, and that the sporadic form of Creutzfeldt-Jakob disease occurs spontaneously with no evidence of natural transmission. This epidemiologic scenario on the origin of BSE has important implications for prevention of the disease in BSE-free countries. Mainly, emphasis needs to put on practices of feeding animal protein to cattle rather than in reducing the prevalence of sheep scrapie. If BSE is already present in the cattle population, the major threat becomes feeding cows to cows.

Looking for bovine spongiform encephalopathy

J Am Vet Med Assoc 200 (3): 257 (1992) 
Marsh RF

Epidemiological and experimental studies on a new incident of transmissible mink encephalopathy.

J Gen Virol 72 ( Pt 3): 589-594 (1991) 
Marsh RF, Bessen RA, Lehmann S, Hartsough GR
Department of Veterinary Science, University of Wisconsin-Madison 53706. 

Epidemiological investigation of a new incident of transmissible mink encephalopathy (TME) in Stetsonville, Wisconsin, U.S.A. in 1985 revealed that the mink rancher had never fed sheep products to his mink but did feed them large amounts of products from fallen or sick dairy cattle. To investigate the possibility that this occurrence of TME may have resulted from exposure to infected cattle, two Holstein bull calves were injected intracerebrally with mink brain from the Stetsonville ranch. Each bull developed a fatal spongiform encephalopathy 18 and 19 months after inoculation, respectively, and both bovine brains passaged back into mink were highly pathogenic by either intracerebral or oral inoculation. These results suggest the presence of a previously unrecognized scrapie-like infection in cattle in the United States.

Comments on bovine spongiform encephalopathy

J Am Vet Med Assoc 197 (4): 441 (1990) 
Marsh RF

Bovine spongiform encephalopathy in the United States

J Am Vet Med Assoc 196 (10): 1677 (1990) 
Marsh RF
Department of Veterinary Science, School of Veterinary Medicine, University of Wisconsin, Madison

Photoreceptor degeneration in experimental transmissible mink encephalopathy of hamsters.

Exp Neurol 96 (3): 727-731 (1987) 
Buyukmihci NC, Goehring-Harmon F, Marsh RF

Hamsters were inoculated intracerebrally with the agent of transmissible mink encephalopathy and developed clerical signs of encephalopathy. Photoreceptor degeneration occurred in all animals examined histologically. The changes were similar to those in scrapie, although less extensive. The findings suggest that either transmissible mink encephalopathy is a mink-adapted form of scrapie or, in rodents, photoreceptor degeneration is a characteristic of infection with agents of the spongiform encephalopathies.

Ocular effects of scrapie agent in hamsters: preliminary observations.

Invest Ophthalmol Vis Sci 16 (4): 319-324 (1977) 
Buyukmihci N, Marsh RF, Albert DM, Zelinski K

Scrapie is caused by one of a group of so-called slow viruses responsible for the subacute spongiform encephalopathies. In the present study, young hamsters were inoculated intracerebrally with hamster-adapted scrapie agent. At termination, all inoculated animals showed signs and central nervous system pathology compatible with scrapie infection. The eyes appeared well developed grossly, but histologically the retina and optic nerve were abnormal. There were varying degrees of thinning of the retina, with the photoreceptor layer being most severely affected. Although the ganglion cell layer was not much different from the controls, the optic nerve appeared more cellular than that of the controls.

Transmissible mink encephalopathy. Reduced spongiform degeneration in aged mink of the Chediak-Higashi genotype.

Lab Invest 34 (4): 381-386 (1976) 
Marsh RF, Sipe JC, Morse SS, Hanson RP

Mink which are 18 months or older and are dying of transmissible mink encephalopathy (TME) have been found to have a marked reduction in spongiform degeneration of the brain if they are homozygous for the Aleutian gene and thus exhibit the autosomal recessive disorder known as the Chediak Higashi (CH) syndrome. CH mink younger than 1 year, and young or old non-CH mink have a typical lesion profile with widespread microvacuolation of the neuropile. Whereas aged CH mink have reduced spongiform degeneration at both the light and electron microscopic level, there is no other apparent alteration in the TME disease process. The length of incubation, clinical signs, astrocytic response, and brain concentration of the TME agent are comparable to those seen in non-CH mink. We conclude that spongiform degeneration is a secondary change in TME and speculate that vacuolation may be the result of lysosomal enzymes causing an increase in ganglioside catabolism.

The subacute spongiform encephalopathies.

Front Biol 44: 359-380 (1976) 
Marsh RF