Atypical/Nor98 Scrapie Infectivity in Sheep Peripheral Tissues

Abstract

Atypical/Nor98 scrapie was first identified in 1998 in Norway. It is now considered as a worldwide disease of small ruminants and currently represents a significant part of the detected transmissible spongiform encephalopathies (TSE) cases in Europe. Atypical/Nor98 scrapie cases were reported in ARR/ARR sheep, which are highly resistant to BSE and other small ruminants TSE agents. The biology and pathogenesis of the Atypical/Nor98 scrapie agent in its natural host is still poorly understood. However, based on the absence of detectable abnormal PrP in peripheral tissues of affected individuals, human and animal exposure risk to this specific TSE agent has been considered low. In this study we demonstrate that infectivity can accumulate, even if no abnormal PrP is detectable, in lymphoid tissues, nerves, and muscles from natural and/or experimental Atypical/Nor98 scrapie cases. Evidence is provided that, in comparison to other TSE agents, samples containing Atypical/Nor98 scrapie infectivity could remain PrP^Sc negative. This feature will impact detection of Atypical/Nor98 scrapie cases in the field, and highlights the need to review current evaluations of the disease prevalence and potential transmissibility. Finally, an estimate is made of the infectivity loads accumulating in peripheral tissues in both Atypical/Nor98 and classical scrapie cases that currently enter the food chain. The results obtained indicate that dietary exposure risk to small ruminants TSE agents may be higher than commonly believed. Following the bovine spongiform encephalopathy (BSE) crisis and the identification of its zoonotic properties, a sanitary policy has been implemented based on both eradication of transmissible spongiform encephalopathies (TSE) in food-producing animals and exclusion of known infectious materials from the food chain. Atypical/Nor98 scrapie is a prion disease of small ruminants identified worldwide. Currently it represents a significant part of the TSE cases detected in Europe. The restricted tissue distribution of Atypical/Nor98 scrapie agent in its natural host and the low detected prevalence of secondary cases in affected flocks meant that it is believed to be a poorly transmissible disease. This has led to the view that Atypical/Nor98 scrapie is a spontaneous disorder for which human and animal exposure risk remains low. In this study we demonstrate that in affected individuals, Atypical/Nor98 scrapie agent can disseminate in lymphoid tissues, nerves, and muscles, challenging the idea that it is a brain-restricted infectious agent. Evidence for the deficiencies in the current methods applied for monitoring Atypical/Nor98 scrapie is provided that would indicate an underestimation in the prevalence in the general population and in the affected flocks. These elements challenge the hypothesis on the biology of this recently identified TSE agent.