Transmissible spongiform encephalopathies related to bovine spongiform encephalopathy in other domestic and captive wild species

Previous authors: R BRADLEY AND D W VERWOERD

Current authors:
E VALLINO COSTASSA - Doctor in Veterinary Medicine, DVM, PhD, Centre for Animal Encephalopathies (CEA), Istituto Zooprofilattico Sperimentale Piemonte Liguria e Valle d’Aosta, Turin, Italy
T KONOLD - Veterinary Surgeon, Information Officer & Veterinary Research Officer, DrMedVet, PhD, MRCVS, ASU, Pathology Department, APHA Weybridge, Woodham Lane, New Haw, Addlestone, Surrey, KT15 3NB, United Kingdom

GENERAL INTRODUCTION: PRION DISEASES

Excluding human transmissible spongiform encephalopathies (TSEs) and scrapie, the only naturally occurring animal TSEs known in 1985, i.e. before the advent of bovine spongiform encephalopathy (BSE), were transmissible mink encephalopathy of Mustela vison reported in the United States, Canada, Finland, East Germany and USSR²⁸ and chronic wasting disease (CWD) affecting wild cervids. This latter disease, until 2015, had been restricted to United States, Canada and South Korea. In 2016, a prion disease was reported for the first time in Europe in wild reindeer (Rangifer tarandus)⁵ which, although reported to be susceptible to oral challenge with CWD prions,³¹ had not previously been found to be naturally infected. Extended surveillance in Norway led to the detection of more cases in reindeer as well as red deer (Cervus elaphus) and moose (Alces alces).¹⁰ A positive moose was subsequently also identified in Finland; however, the pathological phenotype of the moose cases was different from reindeer. Further investigation into these cases are currently ongoing to determine the origin and cause of European cases.

In 1986, just before the first case of BSE was confirmed, a spongiform encephalopathy in a captive nyala (Tragelaphus angasi) in the UK was confirmed by microscopic examination of the brain. This was a prelude to other cases in captive wild members of the family Bovidae, such as greater kudu (Tragelaphus strepsiceros), Arabian oryx (Oryx leucoryx), eland (Taurotragus oryx),  gemsbok (Oryx gazella), nyala (Tragelaphus angasi), scimitar-horned oryx (Oryx dammah) and bison (Bison bison) as well as domestic Ankole cattle identified during the BSE epidemic.²⁰ All these species were presumably exposed to contaminated meat and bone meal (MBM) derived from ruminants. Indeed, experimental transmission of kudu and nyala brain homogenates into mice showed pathology similar to BSE,²³ supporting the hypothesis that spongiform encephalopathy in exotic ungulates was related to BSE.

It has been shown that classical BSE can be transmitted to red deer by intracerebral and oral routes. The clinical signs were similar to CWD but – unlike CWD – disease-associated prion protein (PrP^Sc) was not detected in lymphoid tissue. If BSE cases arose naturally in these animals, they could have been distinguished by the current confirmatory post-mortem tests.²⁷

The possible spread of the BSE agent to small ruminants by feeding contaminated feedstuffs was a major concern in Europe, and TSE surveillance in small ruminants was increased as a consequence. Passage of the BSE agent in ‘new’ hosts may change strain properties and make it difficult to recognize the original strain and thereby increase the risk of epidemic spread. To date, there are no reports of naturally occurring BSE in sheep but since 2005, two natural BSE cases have been reported in goats.^{12, 38} Experimental studies to better characterize the classical BSE phenotype in the event that it is transmissible to sheep and goats have shown that both species are readily infected with the classical BSE agent and that PrP^Sc distribution is very similar to that observed in classical scrapie. This results in infectivity in all lymphoid tissues^{13, 14, 21} with some interspecies variability. Clinical signs were similar to classical scrapie in both species, with pruritus as a consistent finding in sheep.^{24, 25} Reduced susceptibility was associated with increasing age in sheep,¹⁹ and prion protein genotypes that confer resistance to classical scrapie, such as K₂₂₂ in goats and A₁₃₆R₁₅₄R₁₇₁ in sheep, also appeared to be associated with increased resistance to classical BSE.^{1, 30} Although classical BSE can be naturally transmitted in an experimental setting, the efficiency to transmit maternally and laterally was low.²² Thus, if individual sheep were infected naturally by consumption of BSE-contaminated meat and bone meal, it probably would not have been passed on sufficiently to other sheep to remain present in the flock.

In 1990, a naturally occurring TSE in a domestic cat was reported for the first time in the UK, soon to be followed by several other reports.¹⁵ Since 1990, 89 cases of feline spongiform encephalopathy (FSE) have been recorded in domestic cats in Great Britain, one in Ireland, one in Norway, one in Liechtenstein, one in Italy and two in Switzerland.¹¹ The origin of infection in all cases appears most likely to be feed, but the precise source is unknown because of the varied diets of affected cats. Nevertheless, TSE-infected MBM seems a likely, if unproven, source.

All the cases of FSE described in cats demonstrate that most of the affected animals were male, of common European breed and between 4 and 9 years of age. The first signs consisted of behavioral changes characterized by sudden aggression or shyness, apprehension, hyperesthesia to auditory and tactile stimuli, hypersalivation, polyphagia and polydipsia. Movement abnormalities included ataxia, hypermetria and head tremor.^{9, 15} The immunohistochemical findings of PrP^Sc in the tissues of several domestic cats with FSE have been reported.³⁵ Although PrP^Sc in the brains of up to 14 cats was consistent, it was rarely found in lymphoreticular tissues, including the spleen and the intestine (Peyer’s patches and/or myenteric plexus), and then only in small amounts. However, PrP^Sc was found in the glomeruli of the kidneys of 13 cats (100 per cent of those examined).

More recently, an immunohistochemical study of PrP^Sc distribution in two shorthair cats revealed strong immunolabelling in the brain, retina, optic nerve, pars nervosa of the pituitary gland, trigeminal ganglia, and small amounts in the myenteric plexus of the small intestine (duodenum, jejunum) and the medulla of the adrenal glands.¹⁸

The peak occurrence of reported cases of FSE in domestic cats in the UK was in 1994 (16 cases). Since then the prevalence of reported cases has diminished progressively. That supports the view that the ban on feeding specified risk materials (SRM) was probably effective in preventing new exposures.

The concurrent appearance of a case of conventional sporadic Creutzfeldt-Jakob disease in a human in Italy and FSE in his pet cat has been reported.⁴¹ It was unclear whether this is merely a coincidence of each host acquiring infection from separate sources, or of one host contracting infection from the other, or whether each was infected from a common source.

Feline spongiform encephalopathy has also been reported in 21 captive wild felids including several species naturally resident in Africa: six cheetahs (Acinonyx jubatus), five lions (Panthera leo), three tigers (Panthera tigris), three pumas (Puma concolor), three ocelots (Leopardus pardalis), one Asian leopard cat (Prionailurus bengalensis) and one Asian golden cat (Catopuma temminckii).¹¹ Almost all of these FSE cases occurred in animals that were kept in or originated from the UK. The epidemiological, clinical and pathological features of a case of FSE in a cheetah exported from the UK to France have been described.³ The origin of infection in most of these cases seems likely to be from TSE infected, uncooked carcass material from cattle that contained central nervous tissue. Similar to the situation in domestic cats, most of the FSE cases in captive wild felids were born before the specified bovine offals (SBO) ban was in place in the UK that prohibited the feeding of bovine offal, or any feeding stuff containing specified bovine offal to animals.

The temporal and geographical coincidence of these reported TSEs of domestic cats and wild Bovidae and Felidae with the BSE epidemic in the UK indicates a cattle origin although that has not been proven.

In France, captive primates such as rhesus monkeys (Macaca mulatta) and lemurs (Eulemur spp.)  developed TSE naturally, and it is suggested that this occurred as a result of dietary exposure to TSE infection in feed imported from the UK before controls were in place.^{6, 7} Similar clinical signs and pathology were described after experimental oral exposure of lemurs to the BSE agent.⁶ Bovine spongiform encephalopathy was successfully transmitted by combined intracerebral and intraperitoneal inoculation to marmosets (Callithrix jacchus).² The occurrence and neuropathology of a scrapie-like spongiform encephalopathy in red-necked ostriches (Struthio camelus) in a German zoo has been reported.³⁶ However, the true nature of this disease is in doubt, given that the immunohistochemical analysis performed with monoclonal antibody F99/97.6.1 failed to demonstrate specific PrP accumulation.⁴ Oral and combined intracerebral and intraperitoneal inoculation of chickens with classical BSE brain failed to produce prion disease.³²

It has been demonstrated that pigs are susceptible to classical BSE by parenteral inoculation but oral inoculation with amounts comparable to the maximum daily intake of MBM in rations for pigs at the time failed to produce disease.⁴⁰ It was noted that challenged and control pigs which were exposed to infection but failed to develop disease had vacuolar changes in their brains, most notably in the superficial layers of the rostral colliculus. These changes were undistinguishable from those in BSE-experimentally affected pigs.³⁴ However, there was no evidence of prion disease when pig brain suspensions prepared from pig brain with vacuolar changes were inoculated into pigs.²⁶ Successful intracerebral transmission of brains belonging to sheep infected with classical BSE into pigs has also been reported. This produced widespread PrP^Sc accumulation and infectivity in peripheral tissues of pigs.^{16, 17} All these transmission studies in pigs demonstrated that BSE-derived agents were able to replicate efficiently in various extraneural tissues, thus justifying the measures taken to prevent entry of the BSE agent into the feed chain.

It is important to note that all cases of naturally occurring TSE likely to have resulted from exposure to the classical BSE agent, in particular they have probably been exposed to feed containing MBM or have been fed uncooked bovine material. Based on this feedborne hypothesis, an early ban (1988) of the feeding of MBM to ruminants was the first effective measure applied in the UK. Moreover, a new measure including the removal of all offal from the food and feed chains was enforced and, with European Regulation (EC) 999/2001, an extended total feed ban preventing the administration of feed containing mammalian-derived protein to all farmed animals was enforced within Europe.⁸ Thanks to these measures, the occurrence of classical BSE and of TSE related to classical BSE was dramatically reduced.

Current knowledge of atypical BSE strains in small ruminants is founded on experimental studies. These studies were necessary to assess whether the experimentally produced disease had similarities to or could be distinguished from known naturally occurring TSEs in small ruminants. L-BSE was successfully transmitted via intracerebral inoculation of sheep with various prion protein genotypes.^{29, 33, 37} These studies demonstrated

1. that properties of the agent did not change and still resembled L-type BSE in the diagnostic tests,
2. that PrP^Sc accumulation was mainly limited to the central and peripheral nervous system and rarely detected in lymphoid tissue, and
3. that the clinical presentation was mainly characterized by cataplexy (collapse with reduced muscle tone).

Goats intracerebrally inoculated with L-type BSE developed clinical disease with tremor, ataxia, dullness and pruritus (scrapie-like), with no detectable peripheral PrP^Sc accumulation and a band of low molecular mass in the Western blot, which is a feature of L-type BSE.³⁹ All these studies demonstrated that small ruminants are susceptible to atypical (L-type) strains of BSE; however, these forms can be detected easily and distinguished from classical BSE or scrapie by the confirmatory methods currently in use for surveillance of TSEs in sheep and goats.

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