Inconsistent detection of PrP in extraneural tissues of cats with feline spongiform encephalopathy

Feline spongiform encephalopathy (FSE), a transmissible spongiform encephalopathy or prion disease of cats, first reported in Great Britain in 1990, is believed to result from the consumption of food contaminated by the agent of bovine spongiform encephalopathy (BSE). The accumulation of PrP in non-neural tissues of cats diagnosed as suffering from FSE was investigated by immunohistochemistry. In the majority of the cats no disease-specific PrP was detected in lymphoid tissues. Small amounts of PrP were detected in the spleen of only two of 13 samples examined, in Peyer's patches of one of the two cases for which suitable material was available, but in the myenteric plexus of all four cats in which sections of intestine were examined. In addition PrP immunostaining was found in the kidney of all the cats with FSE whose kidneys were examined.     

Cows, cats, and FSE: death penalty justified?

Transmissible spongiform encephalopathies affect a number of mammalian species. The most common spongiform encephalopathies are scrapie in sheep and Bovine Spongiform Encephalopathy (BSE) in cattle. Feline Spongiform Encephalopathy (FSE) is a related disorder in domestic cats. Because of the link between BSE and FSE, cats are put on a par with cattle, in terms of politics and regulations. In the Netherlands, when a case of BSE is found on a farm, not only the ruminants, but also the cats are taken away for post-mortem examination. So far, the cats examined have always been negative for FSE. There are no scientific reasons for destroying the cats on farms where BSE has been found.     

Neuropathology of italian cats in feline spongiform encephalopathy surveillance

Feline spongiform encephalopathy (FSE) is a transmissible spongiform encephalopathy associated with the consumption of feedstuffs contaminated with tissue from bovine spongiform encephalopathy-affected cattle and characterized by the accumulation in the central nervous system of an abnormal isoform of the prion protein (PrP(sc)). Clinically, it presents as a progressive fatal neurologic syndrome that is not easily distinguished from other feline neurologic conditions. Most cases of FSE have been reported in England, where it was first detected in 1990, but a few cases have been reported from other European countries. To identify possible cases of FSE in Italy, the Italian Ministry of Health funded a 2-year surveillance project during which the brains from 110 domestic cats with neurologic signs were evaluated histologically for spongiform encephalopathy and immunohistochemically to detect PrP(sc). Although no cases of FSE were found, the study proved useful in monitoring the Italian cat population for other neurologic diseases: neoplasia (21.8%), toxic-metabolic encephalopathy (18.2%), granulomatous encephalitis (15.5%), suppurative encephalitis (4.6%), trauma (3.6%), circulatory disorders (3.6%), degeneration (2.7%), nonsuppurative encephalitis (2.7%), and neuromuscular diseases (1.8%). No histologic lesions were found in 20% of the brains, and samples from 5.5% of the cats were rejected as unsuitable.     

Pathogenesis of BSE

Before the emergence of bovine spongiform encephalopathy (BSE) and recognition of its zoonotic potential, the major example of the transmissible spongiform encephalopathies (TSEs) of animals was scrapie of sheep. But there is no evidence that scrapie transmits naturally to any species other than sheep and goats. The pathogenesis of scrapie has been studied most in experimental laboratory rodent species. In most experimental models of scrapie, after peripheral non-neural routes of infection, replication of the agent can first be detected in lymphoreticular system (LRS) tissue. When the route of introduction of agent into the body is localized, initial involvement will be in LRS tissue draining the infection site. Thereafter, there is a striking amplification of the agent in the LRS and spread by lymphatic/haematogenous routes, giving widespread dissemination in the LRS. This precedes replication in the CNS, but is not the means by which infection reaches the CNS. There is now substantial evidence from experimental models of scrapie that involvement of the CNS is by peripheral nervous system (PNS) pathways. In some models employing oral exposure the earliest localized LRS replication is in the gut-associated lymphoid tissue (GALT) and autonomic PNS routing to the CNS has been implicated. However, the relative importance of different routes of spread of TSEs within the body is determined by a number of host- and agent-dependent factors and, therefore, generalizations from an experimental model to a natural disease across a species barrier may not be appropriate. With the occurrence of BSE and recognition of its food-borne route of transmission via meat and bone meal, has come greater awareness of the probable importance of the oral route of infection in ruminant species affected by TSEs. In consequence, studies have increasingly focused on the natural host species to examine pathogenetic events.     

Pathogenesis of BSE

Before the emergence of bovine spongiform encephalopathy (BSE) and recognition of its zoonotic potential, the major example of the transmissible spongiform encephalopathies (TSEs) of animals was scrapie of sheep. But there is no evidence that scrapie transmits naturally to any species other than sheep and goats. The pathogenesis of scrapie has been studied most in experimental laboratory rodent species. In most experimental models of scrapie, after peripheral non-neural routes of infection, replication of the agent can first be detected in lymphoreticular system (LRS) tissue. When the route of introduction of agent into the body is localized, initial involvement will be in LRS tissue draining the infection site. Thereafter, there is a striking amplification of the agent in the LRS and spread by lymphatic/haematogenous routes, giving widespread dissemination in the LRS. This precedes replication in the CNS, but is not the means by which infection reaches the CNS. There is now substantial evidence from experimental models of scrapie that involvement of the CNS is by peripheral nervous system (PNS) pathways. In some models employing oral exposure the earliest localized LRS replication is in the gut-associated lymphoid tissue (GALT) and autonomic PNS routing to the CNS has been implicated. However, the relative importance of different routes of spread of TSEs within the body is determined by a number of host- and agent-dependent factors and, therefore, generalizations from an experimental model to a natural disease across a species barrier may not be appropriate. With the occurrence of BSE and recognition of its food-borne route of transmission via meat and bone meal, has come greater awareness of the probable importance of the oral route of infection in ruminant species affected by TSEs. In consequence, studies have increasingly focused on the natural host species to examine pathogenetic events.     

Atypical scrapie in a Swiss goat and implications for transmissible spongiform encephalopathy surveillance.

Different types of transmissible spongiform encephalopathies (TSEs) affect sheep and goats. In addition to the classical form of scrapie, both species are susceptible to experimental infections with the bovine spongiform encephalopathy (BSE) agent, and in recent years atypical scrapie cases have been reported in sheep from different European countries. Atypical scrapie in sheep is characterized by distinct histopathologic lesions and molecular characteristics of the abnormal scrapie prion protein (PrP(sc)). Characteristics of atypical scrapie have not yet been described in detail in goats. A goat presenting features of atypical scrapie was identified in Switzerland. Although there was no difference between the molecular characteristics of PrP(sc) in this animal and those of atypical scrapie in sheep, differences in the distribution of histopathologic lesions and PrP(sc) deposition were observed. In particular the cerebellar cortex, a major site of PrP(sc) deposition in atypical scrapie in sheep, was found to be virtually unaffected in this goat. In contrast, severe lesions and PrP(sc) deposition were detected in more rostral brain structures, such as thalamus and midbrain. Two TSE screening tests and PrP(sc) immunohistochemistry were either negative or barely positive when applied to cerebellum and obex tissues, the target samples for TSE surveillance in sheep and goats. These findings suggest that such cases may have been missed in the past and could be overlooked in the future if sampling and testing procedures are not adapted. The epidemiological and veterinary public health implications of these atypical cases, however, are not yet known.     

Bovine spongiform encephalopathy and human health

Because bovine spongiform encephalopathy (BSE) has probably been caused by accidental transmission of the transmissible agent of sheep scrapie there is concern that humans may be at risk from BSE. Epidemiological and experimental evidence is examined which suggests that this is unlikely.     

A histopathologic and immunohistochemical review of archived UK caprine scrapie cases

In 2005, a prion disease identified in a goat from France was reported to be consistent with disease from the bovine spongiform encephalopathy (BSE) agent. Subsequent retrospective examination of UK goat scrapie cases led to the identification of one potentially similar, but as yet unconfirmed, case from Scotland. These findings strengthened concerns that small ruminant populations exposed to the BSE agent have become infected. The lack of data relating specifically to scrapie in goats has been contributory to past assumptions that, in general, sheep and goats respond similarly to prion infections. In this study, brain material from 22 archived caprine scrapie cases from the UK was reviewed by histopathology and by immunohistochemical examination for accumulations of disease-specific prion protein (PrP(Sc)) to provide additional data on the lesions of caprine scrapie and to identify any BSE-like features. The vacuolar change observed in the goats was characteristic of transmissible spongiform encephalopathies in general. PrP(Sc) immunohistochemical morphologic forms described in scrapie and experimental BSE infections of sheep were demonstrable in the goats, but these were generally more extensive and variable in PrP(Sc) accumulation. None of the cases examined showed a PrP(Sc) immunohistochemical pattern indicative of BSE.     

Susceptibility of cattle to first-passage intracerebral inoculation with chronic wasting disease agent from white-tailed deer

Fourteen, 3-month-old calves were intracerebrally inoculated with the agent of chronic wasting disease (CWD) from white-tailed deer (CWDwtd) to compare the clinical signs and neuropathologic findings with those of certain other transmissible spongiform encephalopathies (TSE, prion diseases) that have been shown to be experimentally transmissible to cattle (sheep scrapie, CWD of mule deer [CWDmd], bovine spongiform encephalopathy [BSE], and transmissible mink encephalopathy). Two uninoculated calves served as controls. Within 26 months postinoculation (MPI), 12 inoculated calves had lost considerable weight and eventually became recumbent. Of the 12 inoculated calves, 11 (92%) developed clinical signs. Although spongiform encephalopathy (SE) was not observed, abnormal prion protein (PrPd) was detected by immunohistochemistry (IHC) and Western blot (WB) in central nervous system tissues. The absence of SE with presence of PrPd has also been observed when other TSE agents (scrapie and CWDmd) were similarly inoculated into cattle. The IHC and WB findings suggest that the diagnostic techniques currently used to confirm BSE would detect CWDwtd in cattle, should it occur naturally. Also, the absence of SE and a distinctive IHC pattern of CWDwtd and CWDmd in cattle suggests that it should be possible to distinguish these conditions from other TSEs that have been experimentally transmitted to cattle.     

Recently described scrapie-like encephalopathies of animals: case definitions.

Since 1986, naturally occurring scrapie-like encephalopathies have been described in the United Kingdom in domestic cattle, in five species of captive exotic bovids and in domestic cats. The disease in domestic cattle, bovine spongiform encephalopathy, has been characterised by all currently available diagnostic criteria as a transmissible spongiform encephalopathy or 'prion' disease, and has been shown to have a dietary origin. The pathology in the other species is also entirely consistent with the scrapie-like diseases. The contemporaneous occurrence in the UK of such disease in these species suggests a close epidemiological association. The diagnostic criteria of the scrapie-like encephalopathies of animals are reviewed in the light of experience with the recent extension of their natural host range.     

Elevated manganese levels in blood and central nervous system occur before onset of clinical signs in scrapie and bovine spongiform encephalopathy

Prion diseases, or transmissible spongiform encephalopathies, are neurodegenerative diseases that can only be accurately diagnosed by analysis of central nervous system tissue for the presence of an abnormal isoform of the prion protein known as PrP(Sc). Furthermore, these diseases have long incubation periods during which there are no clear symptoms but where the infectious agent could still be present in the tissues. Therefore, the development of diagnostic assays to detect a surrogate marker for the presence of prion disease is essential. Previous studies on mice experimentally infected with scrapie, an ovine spongiform encephalopathy, suggested that changes in the levels of Mn occur in the blood and brain before the onset of symptoms of the disease. To assess whether these findings have relevance to the animal diseases scrapie and bovine spongiform encephalopathy, tissues from bovine spongiform encephalopathy- and scrapie-infected cattle and sheep were analyzed for their metal content and compared with values for noninfected animals. In field cases and experimentally infected animals, elevated Mn was associated with prion infection. Although some central nervous system regions showed elevated Mn, other regions did not. The most consistent finding was an elevation of Mn in blood. This change was present in experimentally infected animals before the onset of symptoms. In scrapie-infected sheep, elevated Mn levels occurred regardless of the genotype of the sheep and were even detected in scrapie-resistant sheep in which no symptoms of disease were detected. These findings suggest that elevated blood Mn could be a potential diagnostic marker for prion infection even in the absence of apparent clinical disease.     

Animal spongiform encephalopathies ‐ an update part 1. Scrapie and lesser known animal spongiform encephalopathies

Summary

The present article (part I) reviews recent developments in animal spongiform encephalopathies (SEs), with the exception of bovine spongiform encephalopathy (BSE), which is dealt with in part II.

The article focuses on scrapie and describes epidemiological aspects and the prospects for a preclinical diagnosis. Up to now, confirmatory diagnosis of scrapie depended on histological examination of the brain, collected during post‐mortem examination from sheep with clinical signs of the disease. An altered protein, PrP^Sc, can be detected in the brain of diseased animals. The demonstration of the same protein in the spleen and in peripheral lymph nodes of infected animals seems to offer interesting possibilities of arriving at a method for a preclinical diagnosis, and thus a diagnosis in the live animal. Progress has also been made in our understanding of the relationship between the genetic constitution and susceptibility of the host. Susceptibility is expressed as the survival time of sheep inoculated with scrapie. This was thought to be determined by a single genetic locus designated the Sip gene (scrapie incubation period gene). Putative markers for the two alleles of the Sip gene, sA and pA, have been discovered, consisting of restriction fragment length polymorphisms (RFLPs). In field tests, however, the link between these markers and the length of incubation time was far from consistent. These RFLPs were found to be situated outside the prion‐protein‐co‐ding region of the ovine gene. In later studies, RFLPs were detected inside this region. These markers appear to be more informative, i.e. they correspond with a difference in the length of the scrapie incubation period.

Finally, the article briefly describes recent developments in other, lesser known, animal spongiform encephalopathies: chronic wasting disease and other spongiform encephalopathies in exotic ungulates, transmissible mink encephalopathy, and feline spongiform encephalopathy, focusing on their possible links with scrapie or bovine spongiform encephalopathy.     

Swiss scrapie surveillance. II. Epidemiologic aspects of the detection of neurological diseases in sheep and goats

Monitoring of transmissible spongiform encephalopathy (TSE) in Swiss sheep and goats is based on the examination of animals from different sources. In this study, frequencies and proportions of the different diagnoses were compared between routinely submitted sheep and goats, notified scrapie suspects as well as fallen stock. Meningitis/ encephalitis cases were significantly more frequent (OR = 2.2) in the scrapie suspect group when compared to the routine submissions. Metabolic-toxic encephalopathy was seen more frequently within the fallen stock. Rare neurological diagnoses were more frequent among scrapie suspects and routine submissions when compared to fallen stock. Listeriosis was diagnosed equally frequent among the scrapie suspects and routine submissions but less frequent in fallen stock. Scrapie prevalence among the fallen stock and the routine submissions was 0 (zero), with 95% certainty that prevalence is < 1%. The examined animals are representative for most of the Swiss regions with considerable sheep and goat production. Continuation of the detailed neuropathological examination of small ruminants from these three groups, substituted by actively testing a sufficiently large sample of fallen stock and possibly also healthy-slaughtered adult sheep and goats for transmissible spongiform encephalopathies would ensure a good surveillance within the small ruminant population.     

Scrapie: the risk of its introduction and effects on trade

New Zealand and Australia are fortunate in that they are among the few sheep rearing countries free from scrapie, despite cases in imported sheep in the 1950s. The importance of sheep rearing in the Australasian economies, and the difficulties involved in importing sheep without risking the introduction of scrapie, has meant that there have been very few importations of new blood lines in the last 40 years, and those that have been imported have been through stringent programs designed to ensure freedom from scrapie. While scrapie can be a cause of significant wastage in some sheep rearing situations, its major threat to Australasia is probably to the developing biopharmaceutical industries which, since the emergence of bovine spongiform encephalopathy, have benefitted from an international demand for products guaranteed to be derived from livestock free from the transmissible spongiform encephalopathies. This paper outlines one method which has been used to assess the risk of introducing scrapie as the result of importation of sheep and discusses the difficulty in ascertaining what constitutes an acceptable risk.     

Resistance of cattle to scrapie by the oral route.

Early epidemiological information indicated that bovine spongiform encephalopathy (BSE) originated from scrapie in sheep. The question arose if scrapie in North America would induce a BSE-like disease in cattle. Six years ago, we reported that brain tissue from sheep with scrapie caused a neurologic disease when injected directly into the brains of cattle, but the disease induced was different from BSE as it occurs in the United Kingdom and Europe. Here, we report that cattle fed raw brain or meat and bone meal and tallow prepared from sheep with scrapie remained normal for 8 years after exposure. This work indicates that cattle are highly resistant to North American scrapie by the oral route.     

Approaches to investigating transmission of spongiform encephalopathies in domestic animals using BSE as an example

Bovine spongiform encephalopathy was a novel spongiform encephalopathy, in an hitherto unaffected species, that had characteristics of a point source epidemic, with an agent that could have been incorporated into a wide variety of feedstuffs and iatrogenically administered to na?ve populations, and there was early evidence that it was not restricted to bovines. It was vital to establish, albeit experimentally, which other species might be affected, and whether the epidemic could be maintained by natural transmission, if the source was removed. In contrast, scrapie has been endemic throughout Great Britain for centuries, is maintained naturally (even if we don't know exactly how) and has a known host range. The principles, process and integration of evidence from different types of studies, however, are similar for both of these transmissible spongiform encephalopathies (TSE) and can be applied to any emerging or suspected spongiform encephalopathy. This review discusses the experimental approaches used to determine TSE transmissibility and infectivity and how they relate to natural disease and control measures.     

应用线粒体DNA鉴定动物源性饲料成分研究进展

为避免牛海绵状脑病和羊痒病疫区的蛋白饲料进口造成畜牧业上的经济损失,世界各国纷纷开展用分子生物学方法检测牛、羊源性蛋白饲料,本文就运用分子生物学方法有效检测动物物种间线粒体DNA特异性以确认动物源性蛋白饲料成分的来源作出阐述。     

Chronic wasting disease

Chronic wasting disease (CWD) is a unique transmissible spongiform encephalopathy (TSE) of mule deer (Odocoileus hemionus), white-tailed deer (O. virginianus), and Rocky Mountain elk (Cervus elaphus nelsoni). The natural history of CWD is incompletely understood, but it differs from scrapie and bovine spongiform encephalopathy (BSE) by virtue of its occurrence in nondomestic and free-ranging species. CWD has many features in common with scrapie, including early widespread distribution of disease-associated prion protein (PrP(d)) in lymphoid tissues, with later involvement of central nervous system (CNS) and peripheral tissues. This distribution likely contributes to apparent efficiency of horizontal transmission and, in this, is similar to scrapie and differs from BSE. Clinical features and lesions of CWD are qualitatively similar to the other animal TSEs. Microscopically, marked spongiform lesions occur in the central nervous system (CNS) after a prolonged incubation period and variable course of clinical disease. During incubation, PrP(d) can be identified in tissues by antibody-based detection systems. Although CWD can be transmitted by intracerebral inoculation to cattle, sheep, and goats, ongoing studies have not demonstrated that domestic livestock are susceptible via oral exposure, the presumed natural route of exposure to TSEs. Surveillance efforts for CWD in captive and free-ranging cervids will continue in concert with similar activities for scrapie and BSE. Eradication of CWD in farmed cervids is the goal of state, federal, and industry programs, but eradication of CWD from free-ranging populations of cervids is unlikely with currently available management techniques.     

Feline spongiform encephalopathy: fibril and PrP studies.

The brains from 18 cats were examined for the presence of the fibrils and modified PrP protein which are molecular diagnostic markers for scrapie-like diseases. Thirteen cats were referred with clinical neurological signs potentially indicative of feline spongiform encephalopathy (FSE). Of these, five had histopathological changes of FSE, five had other lesions of the central nervous system, and in three the brain was normal. The remaining five cats had no clinical neurological signs and were selected as controls. Fibrils and modified PrP protein were found in the brains of the five cats with FSE and in one of the cats with neurological signs but no histopathological changes in the central nervous system. Fibrils were present in the absence of modified PrP in the brains of two cats, one with neurological signs and a histologically confirmed meningioma, and one with no neurological signs and a histologically normal brain.     

State-of-the-art review of goat TSE in the European Union, with special emphasis on PRNP genetics and epidemiology

Scrapie is a fatal, neurodegenerative disease of sheep and goats. It is also the earliest known member in the family of diseases classified as transmissible spongiform encephalopathies (TSE) or prion diseases, which includes Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy (BSE), and chronic wasting disease in cervids. The recent revelation of naturally occurring BSE in a goat has brought the issue of TSE in goats to the attention of the public. In contrast to scrapie, BSE presents a proven risk to humans. The risk of goat BSE, however, is difficult to evaluate, as our knowledge of TSE in goats is limited. Natural caprine scrapie has been discovered throughout Europe, with reported cases generally being greatest in countries with the highest goat populations. As with sheep scrapie, susceptibility and incubation period duration of goat scrapie are most likely controlled by the prion protein (PrP) gene (PRNP). Like the PRNP of sheep, the caprine PRNP shows significantly greater variability than that of cattle and humans. Although PRNP variability in goats differs from that observed in sheep, the two species share several identical alleles. Moreover, while the ARR allele associated with enhancing resistance in sheep is not present in the goat PRNP, there is evidence for the existence of other PrP variants related to resistance. This review presents the current knowledge of the epidemiology of caprine scrapie within the major European goat populations, and compiles the current data on genetic variability of PRNP.