Disease phenotype in sheep after infection with cloned murine scrapie strains

Abstract

Prion diseases exhibit different disease phenotypes in their natural hosts and when transmitted to rodents, and this variability is regarded as indicative of prion strain diversity. Phenotypic characterization of scrapie strains in sheep can be attempted by histological, immunohistochemical and biochemical approaches, but it is widely considered that strain confirmation and characterization requires rodent bioassay. Examples of scrapie strains obtained from original sheep isolates by serial passage in mice include ME7, 79A, 22A and 87V. In order to address aspects of prion strain stability across the species barrier, we transmitted the above murine strains to sheep of different breeds and susceptible Prnp genotypes. The experiment included 40 sheep dosed by the oral route alone and 36 sheep challenged by combined subcutaneous and intracerebral routes. Overall, the combined route produced higher attack rates (~100%) than the oral route (~50%) and 2–4 times shorter incubation periods. Uniquely, 87V given orally was unable to infect any sheep. Overall, scrapie strains adapted and cloned in mice produce distinct but variable disease phenotypes in sheep depending on breed or Prnp genotype. Further re-isolation experiments in mice are in progress in order to determine whether the original cloned murine disease phenotype will reemerge.

Keywords: :

• biological properties
• interspecies transmission
• prion protein
• Scrapie diversity
• species barrier
• strain typing

AUTHOR:

Please cite reference 34 in the text. Citations for references 28-31 appear to be out of order and can be corrected upon inclusion of the reference 34 citation.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

The authors greatly appreciate the help provided by Prof. Nora Hunter (Roslin Institute and Royal (Dick) School of Veterinary Studies) with the supply of the cloned murine strains used to generate the inocula. The excellent technical support in immunohistochemistry from Mrs. Lynne Algar, Ms. Ann Dunachie and Ms. Maria Oliva. Finally, the authors thank Dr. James Hope’s critical reading of the manuscript.