Silent Propagation of Classical Scrapie Prions in Homozygous K₂₂₂ Transgenic Mice

Classical scrapie affects sheep and goats. To control prevalence in sheep, the European Union initiated breeding programs targeting resilient genotypes. Although certain goat polymorphisms, such as Q₂₂₂K, are linked to resistance, specific breeding programs have not been implemented. Hemizygous transgenic mice carrying the goat K₂₂₂ cellular prion protein (PrP) allele (K₂₂₂-Tg516) exhibited resistance to several classical scrapie isolates. We inoculated homozygous K₂₂₂-Tg516 and Q₂₂₂-Tg501 mice with various scrapie isolates. Homozygous K₂₂₂-Tg516 mice reached the end of their lifespan without exhibiting clinical signs; we observed brain proteinase K-resistant PrP accumulation in those mice that was lower than in Q₂₂₂-Tg501 mice. Histologically, K₂₂₂-Tg516 brains lacked prion-related lesions, except for the presence of few isolated scrapie PrP plaques in cases of isolates highly adapted to the K₂₂₂-PrP^C environment. Our findings caution against including that polymorphism in breeding programs, because it could lead to emergence of asymptomatic silent prion carriers of classical scrapie among goat populations.