TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES: THE ROLE OF GENETICS, STRAIN VARIATION, AND ENVIRONMENTAL CONTAMINATION IN DISEASE CONTROL
Location: Animal Diseases Research
Title: Transmissibility of caprine scrapie in ovine transgenic mice
Submitted to: BioMed Central (BMC) Veterinary Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: April 2, 2012
Publication Date: April 2, 2012
Citation: Orourke, K.I., Schneider, D.A., Spraker, T.R., Dassayanake, R., Highland, M., Zhuang, D., Truscott, T.C. 2012. Transmissibility of caprine scrapie in ovine transgenic mice. BioMed Central (BMC) Veterinary Research. 8:42.
Interpretive Summary: The ovine scrapie eradication program in the US and Canada is based on the relatively consistent finding that prion genotype is associated with relative disease resistance and that infection is spread through exposure to shed placentas from infected ewes. Caprine scrapie, the related disorder of domestic goats, is less well characterized. The goat prion gene is highly polymorphic and the effect of most polymorphisms on disease susceptibility and incubation time is not known. The disease appears to be transmitted from sheep to goats in commingled herds and among goats in an infected flock, although the modes of transmission are not known. No data on strain variation are available. Given the limited number of infected goats reported in the US, a suitable rodent model for examining distribution of infection prions in goats of varying genotypes or with different clinical presentations will be helpful. In this study, we describe the incubation time, lesion profile, and PrP-sc distribution in the brain of Tg338 mice, a well characterized transgenic mouse line expressing an ovine prion allele. First passage incubation times varied widely but second passage intervals were short and consistent. Examination of brain by histology and immunologic assays demonstrated patterns similar to but not identical to those observed in mice inoculated with classical scrapie. Spleens of mice inoculated by the intracerebral route were positive by western blot analysis. Following validation of the model in comparison to bioassay in goats, the Tg338 mouse will be useful in caprine scrapie transmission and strain typing studies.
Scrapie is a transmissible spongiform encephalopathy or prion disease of domestic sheep and goats. The current US and Canadian control programs are based on diagnosis by identification of abnormal prion protein in brain or lymphoid tissues with selective culling of genetically susceptible sheep exposed to an infected ewe at lambing. These measures are based on several decades of observation on experimentally and naturally infected sheep and in rodent bioassay models. In particular, transgenic mice in which the murine PRNP gene (encoding the cellular prion protein precursor) is replaced by the highly susceptible ovine VRQ allele have been useful for discrimination of atypical strains and identification of tissues with infectious potential. Caprine scrapie is reported in domestic goats but the effect of PRNP genotypes and the potential transmission modes are not well characterized. No rodent model for caprine scrapie has been described. In this manuscript, we describe the use of Tg338 mice, bred from a well characterized ovine PRNP transgenic mouse line, as an experimental host for caprine scrapie. Following experimental intracerebral inoculation, survival curves for primary passage reflected the variability expected when crossing the species barrier. However, second passage incubation times were short and reproducible. Brains from terminally affected mice were subjected to histologic description, paraffin embedded tissue blotting, immunohistochemistry and western blotting. The profiles were similar to that observed in sheep but not identical. Further, PrP-Sc was identified in spleens, demonstrating distribution through the lymphoreticular system even in mice inoculated by the intracerebral route. This line is therefore suitable for strain characterization that includes the critical elements of lesion profile, glycoform analysis, and lymphotropism.