Bovine Spongiform Encephalopathy (BSE) – Infectious, Contagious, Zoonotic or Production Disease?

Abstract

In 1986, a new progressive neurological condition similar to scrapie of sheep and goats was recognised in cattle in the United Kingdom (UK), and was named bovine spongiform encephalopathy (BSE). There is an ongoing discussion whether BSE should be classified as infectious, contagious, or zoonotic, and if it fits the definition of a production disease. The objective of this work is to briefly describe the main characteristics of transmissible spongiform encephalopathies (TSE), to review the epidemiology of BSE, and to address the question of how to classify BSE. TSEs are characterised as chronic wasting diseases with spongiform vacuolation and the accumulation of infectious prion protein (PrP^Sc) in the central nervous system. TSE infectivity is very difficult to inactivate. Cattle BSE most likely originated from sheep scrapie, although this will remain to be an issue for debate. The disease can be transmitted from cattle to a range of species, and has resulted in smaller TSE epidemics in domestic cats, zoo cats and zoo ruminants, and in humans. Transmission in the field occurred through feed containing ruminant-derived protein, and measures to prevent the recycling of infectivity have proven effective to reduce the number of new infections. Mandatory reporting of clinical suspects combined with targeted screening of risk populations is needed to assess the BSE status of a country. Infection studies and the transmissibility to other species classify BSE as infectious and zoonotic. Absence of excretion of the agent, and therefor of horizontal transmission, categorise BSE as non-contagious. However, BSE is a multifactorial infectious disease that is dependent on management factors (mainly feeding), and therefore fits into the broader definition of production diseases.

Introduction

In 1986, a new clinical disease in cattle was recognised in the United Kingdom (UK). It was classified as a progressive neurological condition similar to scrapie of sheep and goats, and was named bovine spongiform encephalopathy (BSE) [49]. Other transmissible spongiform encephalopathies (TSE) had been described before the occurrence of BSE, namely scrapie of sheep and goats (first observed/described as a clinical entity around 1730), a transmissible mink encephalopathy (TME, 1947), a chronic wasting disease of North American deer and elk (CWD, 1978), and the human TSEs sporadic Creutzfeldt-Jakob disease (sCJD, 1920), Gerstmann-Sträussler-Scheinker Syndrom (GSS, 1928), Kuru (1957), and fatal familiar insomnia (FFI, 1986). These TSEs can arise spontaneously (sCJD), be inherited (FFI, GSS), or are naturally or accidentally transmitted (scrapie, Kuru, CWD, BSE). Some of them possess several of these properties [16, 9, 22, 59, 57, 20, 41, 31]. There is an ongoing discussion whether BSE should be classified as infectious, contagious, or zoonotic, and if it fits the definition of a production disease. The objective of this work is to briefly describe the main characteristics of TSEs, to review the epidemiology of BSE, and to address the question of how to classify BSE.

Characteristics of prion diseases

All known TSEs are characterised by an accumulation of prions ("proteinacious infectious particles", PrP) and vacuolation of the CNS in the final stages of the disease. PrP^C is routinely synthesised by various cells, and is metabolised (digested) by proteinase K (enzymes). The infectious prion protein, denoted PrP^Sc or PrP^res, is partly proteinase K resistant. It forms oligomers, accumulates mainly in the cells of the CNS, and results in the specific histopathological changes observed in the differed TSEs [32]. Both PrP^C and PrP^Sc have the same aminoacid sequence, but they have different three-dimensional structures: PrP^C in 42% is composed of structures called alpha helices, and has only a few beta sheets [23]. The infectious PrP^Sc has only 30% alpha helices, and more than 40% beta sheets. The transition of PrP^C to PrP^Sc, based on the prion dimer theory of Prusiner, occurs by merging of a normal (healthy) and an infectious prion molecule to form a PrP^C-PrP^Sc heterodimer, in which the normal PrP^C molecule is restructured into PrP^Sc. After separation of the 2 molecules, 2 new PrP^Sc homodimers have been created which again can convert healthy PrP^C molecules [32]. It still is debated whether PrP^Sc and TSE infectivity are one and the same, or if there is an additional factor "X" (protein, virion, virus?) besides exposure to PrPSc required to result in a TSE infection [48].

TSE infectivity is difficult to destroy (decontaminate). The most efficient method is application of wet heat (autoclaving) after treatment with sodium hydroxide (1–2 M NaOH). Application of dry heat will conserve TSE infectivity, and temperatures up to 600°C have been described as insufficient to fully eliminate it from brain tissue cubes [3, 5]. The commonly used methods to treat MBM during rendering (133°C at 3 bars for 20 minutes) will reduce TSE infectivity by at least 98%, but not always by 100% [43, 45, 38, 44, 46]. TSE infectivity, once excreted, can survive in the environment (soil) for several years, as has been demonstrated with the scrapie agent [4].

Epidemiology of BSE

The origin of BSE (as a cattle disease) is an issue of controversial debate, but it is unlikely that this controversy will ever be resolved. The most widely accepted hypothesis is that cattle BSE originated from sheep scrapie, i.e. that one of the British sheep scrapie strains was recycled with MBM to cattle, and was (or became during recycling) infectious for cattle. After this adaptation, on-going intra-species recycling caused the BSE epidemic in British cattle [35, 47]. Alternatively, a spontaneous mutation in the genome coding for the PrP gene, similar to sporadic CJD in humans, could have resulted in a TSE strain either in sheep or in cattle that was subsequently infectious for – and recycled to – cattle. The introduction of BSE from a wildlife population seems to be a less realistic hypothesis. Large scale recycling of BSE infectivity in the UK became possible after 1970 when changes in the tallow (fat) extraction during MBM rendering from solvent-based (wet, higher temperatures) to pressure-based (dry, lower temperatures) allowed the infectious agent to survive [54, 22].

Epidemiological studies on the clinical BSE cases diagnosed in UK in 1986 and 1987 highlighted the increased risk for BSE on farms that had fed cattle concentrates containing meat and bone meal (MBM). The recycling of ruminant-derived MBM to ruminants and other farm animals via concentrate feed was common practice in the UK and other countries (Fig. 1) [53, 55, 56, 19, 2]. Cattle concentrates contained up to 6% protein of either animal or plant origin. As a consequence of the studies linking MBM use to BSE, this inclusion of MBM into ruminant feed was banned in the UK in July 1988, and in Switzerland in December 1990. These bans resulted in a significant reduction of new infections in cattle born after their implementation, thereby highlighting the importance of controlling this exposure route (Fig. 2). The secondary increase in BSE cases by birth cohort seen in Switzerland might be the result of an increase in the number of infected cattle reaching clinical levels of disease, and increase of MBM imports from neighbouring European countries, and increase in the surveillance activities since 1999, or a combination of those factors.

Figure 1

BSE infection cycle and exposure of other species to products of cattle origin. Solid arrows (--) indicate direct exposure to cattle-derived products (cattle-derived food, cattle feed), broken arrows (-.-.) indicate exposure to feed produced for pigs or poultry, and dotted arrows (.....) indicate an exposure to feed produced for pets (dogs and cats).

BSE cases born after these MBM bans (denoted BAB cases) documented the presence of other infection routes besides routine inclusion of MBM in cattle concentrates. Cross-contamination of cattle feed with feed for pigs and poultry during production, transportation or storage, and cross-exposure of cattle to pig or poultry feed on mixed-species farms were suggested as additional infection routes (Fig. 1) [18, 19]. The Scientific Steering Committee (SSC) of the European Commission in a geographic BSE risk assessment exercise (GBR) listed several risk factors for BSE propagation (spread within a cattle population) including the structure and intensity of the cattle population and other livestock populations, production and use of ruminant-derived meat-and-bone meal (including feed bans), the use of specified risk material (SRM) and carcasses (including SRM bans) and the rendering industry (structure, technology, rendering parameters) [1, 39]. The most important measures to prevent exposure of cattle to BSE are the ban of feeding ruminant protein back to cattle ("MBM ban"), the exclusion of all high risk material such as brain and spinal cord of cattle and cattle carcasses from MBM production ("SRM ban"), the treatment of produced MBM at 133°C and 3 bars for 20 min (EU standard), and the prevention of cross contamination during feed production and use. Blocking of the known and suspected feed-related routes of BSE transmission has resulted in a documented decline in the number of new infections in subsequent birth cohorts in the UK, in Switzerland (Fig. 2), and in other countries. Due to the long incubation time of BSE, however, it takes several years until the effectiveness of implemented measures to prevent new BSE infections can be reliably assessed.

Figure 2

Proportion of all British (-◆-) and Swiss (-▲-) BSE cases with known birth date (y axis) by birth year (x axis). The immediate drop in cases in the year after the first ban of feeding meat and bone meal to cattle (UK July 1988, CH Dec 1990, as indicated by the arrows) highlight the strong (causal) association between MBM feeding and BSE (data as of August 2001).

Pathogenesis

Experimental oral inoculation of calves and sequential slaughter done in the UK documented that BSE infectivity was only present in the anatomical region of the Peyers patches of the distal ileum at distinct time points during the incubation period, and in the central nervous system (CNS: brain, spinal cord, dorsal root ganglia) late in incubation (few months before clinical disease) and during clinical disease. In cattle, BSE infectivity has not been documented in meat, milk, blood, urine, lymph nodes or any other tissue besides the CNS and the distal ileum wall [25, 42, 51, 52]. One report in which sternal bone marrow isolated from a clinical BSE case in one of the experimentally exposed mice induced a TSE was never reproduced, and was later speculated to have been cross-contamination. Without excretion of the infectious agent during incubation or clinical disease, direct horizontal transmission (from infected to susceptible cattle) does not occur. BSE infectivity levels of CNS tissue from clinically diseased cattle have been titrated in cattle, and there is evidence that 0.1 gram of brain tissue is sufficient to orally infect calves with BSE. Direct intracerebral inoculation of the infectious agent into susceptible mice strains seems to be 500 to 1000 times more efficient than oral exposure of the mice, and this method is used extensively to study the distribution of BSE infectivity in various tissues of experimentally infected animals or field cases, and to differentiate between BSE and other TSE strains.

BSE spread and surveillance

Introduction of the BSE agent into recipient countries has occurred by live animal trade, and by direct or indirect trade between BSE-effected and BSE-free countries with MBM and other products potentially containing BSE infectivity [21, 27, 37]. The GBR done by the EU indicated a rather wide geographic distribution of the disease, and this has been confirmed by the surveillance activities implemented since the year 2000. Domestic BSE cases by now have been detected in all but one of the EU Member States (Sweden) as well as in Switzerland (Table 1). In addition, in 2001 Slovakia (4 cases), Japan (3), the Czech Republic (2) and Slovenia (1) experienced their first domestic BSE cases. Based on the GBR, additional countries such as Albania, Estonia, Hungary, Lithuania, Poland and Cyprus are expected to harbour BSE-infected cattle [39].

Table 1 Implementation of mandatory reporting for bovine spongiform encephalopathy (BSE), year of the first BSE cases, implementation of a targeted screening, total BSE case numbers in 2000 and 2001, and assessment of the overall BSE surveillance system in the European Union Member States and Switzerland as of December 21, 2001.

BSE case detection until 1998 was restricted to the mandatory reporting and subsequent investigation of clinical suspect cases ("passive" surveillance). Since 1999 EU-validated fast screening assays such as the Prionics check Western blot or the BioRad Platelia ELISA have become available as a surveillance tool for targeted "high-risk" cohorts ("active" surveillance). This type of combined passive and active BSE surveillance was implemented in Switzerland in January of 1999, and is mandatory for the EU member states since January 1, 2001 [10–12, 33, 40, 34]. Data from the Swiss surveillance indicated that mandatory suspect reporting captured less than 50% of the detectable BSE cases that were removed from the population [10, 11]. In other countries passive surveillance might have completely missed a low number of clinical BSE cases for some periods of time. In recent years, however, an increase also in the number of clinical BSE cases was seen in continental Europe (Fig. 3) in addition to the cases detected by the passive surveillance. The combination of passive and active surveillance components therefore seem essential to reliably assess the BSE status of a given country or region. However, the EU-validated screening assays rely on the post mortem detection of PrP^Sc in brain tissue (homogenate), and are validated only for cattle with clinical BSE [26, 33, 29, 8]. No BSE test is available for detection of animals during early incubation, and we have to assume that a considerable number of such cattle leaves the population undetected. Some ante mortem tests have been announced in the media, however, none has been commercialised so far.

Figure 3

Proportion of all British (-◆-), Swiss (-▲-) and other European countries combined (-●-) clinical BSE cases (y axis) by year of reporting (x axis). The figures for 2001 were extrapolated from the case numbers observed until November 24, 2001.

Transmission of BSE to other species

Transmission of BSE to other species is possible. This has been documented in experimental infection of several species, but also in the observed FSE epidemic in domestic cats (over 90 cases in the UK reported since 1990), in ruminants and large cats kept in British zoos, and by the epidemic of the new variant of Creutzfeldt-Jakob disease (vCJD) in humans with over 100 cases in the UK and 4 cases reported from France so far [30, 60, 50, 36, 6, 58, 17].

BSE can be orally transmitted to sheep and goats where it results in a TSE very similar to scrapie [14, 15]. No field cases of BSE in sheep have yet been diagnosed, however, differentiation to sheep scrapie is only possible by strain typing in mice bioassays, which takes several years to perform. Attempts to orally infect pigs or poultry with BSE failed so far [7, 13, 24].

Conclusion

BSE is a new disease in cattle. Infectivity can be titrated, and the disease has been transmitted to the same and to other species including cats and humans. This classifies BSE as infectious and zoonotic. However, even cattle in the final stages of (clinical) disease do not actively excrete the infectious agent, and horizontal transmission comparable with that of foot-and-mouth disease (FMD), classical swine fever (CSF) or even sheep scrapie does not occur; the disease therefore is not considered to be contagious. The term "production diseases" traditionally was used exclusively for metabolic diseases that were induced by management practices. More recently, the definition of production diseases has been widened to include other traits such as infertility, and multifactorial diseases such as mastitis and lameness that might involve infectious agents but that are exacerbated by nutritional or management factors [28]. BSE, which is caused by an infectious agent (even though some "infectiologists" might not agree to classify prion diseases as such) and is dependent on management factors, would fit into the broader definition of production diseases. This, however, could be true for the majority of diseases that currently affect our animal production systems.