Commentary: Scrapie revisited

Scrapie is a naturally occurring disease of sheep, which has become the subject of increased scientific and media interest as scrapie contamination of feed was the probable origin of bovine spongiform encephalopathy. Despite research over the past 30 years, the mechanism of transmission of natural scrapie remains uncertain. The literature on natural and experimental scrapie is extensive and at times confusing, with some authors arguing that scrapie is a purely genetic disorder while others maintain that it is an infectious disease. The advances in molecular biology in recent years have provided new information on scrapie, and Ridley and Baker provide a timely review, concluding that maternal transmission of scrapie and other spongiform encephalopathies is a myth.

There is no good evidence of maternal transmission in any of the human spongiform encephalopathies, in experimental spongiform encephalopathy in laboratory species, or in transmissible mink encephalopathy. The occurrence of bovine spongiform encephalopathy in cattle born after the feed ban in 1988 has led to speculation regarding maternal transmission of this disease, but epidemiological evidence provides little support for this hypothesis and concern about possible continuing contamination of cattle feed has led to new legislative measures. Maternal transmission in kudu, a breed of captive zoo ungulate, was originally suspected but is now uncertain.

Only with natural scrapie is there evidence of maternal transmission. However, Ridley and Baker question the evidence that shows infectivity in the placenta of sheep with scrapie, and they provide alternative interpretations of embryo transfer experiments and the important breeding experiments carried out by Dickinson and colleagues.1 There are therefore cogent reasons for reconsidering the importance of maternal transmission in natural scrapie, although as Kimberlin has pointed out maternal transmission may be masked if there is a high level of lateral contagion.2

In scrapie, and other spongiform encephalopathies, the occurrence and phenotype of disease is influenced by host genetics and agent characteristics and by the level of infectious challenge and route of exposure. In scrapie, analysis of the prion protein (PrP) gene in sheep has shown that susceptibility to disease is linked to polymorphisms of the PrP gene. The genetics of scrapie susceptibility, summarised by Ridley and Baker, are complex, with the type of inheritance (dominant, partially dominant, or recessive) varying by breed of sheep. Crucially, there is also evidence of an interaction between host genotype and strain of scrapie agent,3 indicating that selective breeding for resistance to scrapie may be problematic and that regarding scrapie as a simple genetic disease may be an oversimplification.

One of the peculiarities of the epidemiology of scrapie is that the large sheep population in New Zealand has been scrapie free for decades. If scrapie is primarily genetically determined, the current analysis of genotypes of sheep in New Zealand may provide important data—for example, it might be predicted that all tested sheep will be of “resistant” genotype. However, in 1979 Hourrigan and colleagues4 reported the development of scrapie in two out of 20 sheep imported from New Zealand following contact with flocks known to be affected by scrapie, and 39% of the progeny of the inbred New Zealand flock also developed scrapie.

Despite molecular biological research, the mechanism of transmission of natural scrapie remains unclear, and control of this important endemic disease cannot currently be based solely on genetic manipulation. Even if maternal transmission is a myth, the complexities of the interaction between host genetics and agent strain, together with the evidence for lateral transmission,1 2 indicate that eradication of scrapie may be difficult to achieve. One important implication of the paper by Ridley and Baker is that previous assumptions about scrapie may have to be re-evaluated, and further research on the epidemiology and transmission characteristics of the natural disease will be necessary if scrapie is to be eradicated. Even if the epidemic of bovine spongiform encephalopathy declines and disappears early in the next century as predicted, scrapie will remain as a potential source of animal zoonoses in many countries where it is endemic.