Heterozygosity for cervid S138N polymorphism results in subclinical CWD in gene-targeted mice and progressive inhibition of prion conversion.

Abstract

Prions are proteinaceous infectious particles that replicate by structural conversion of the host-encoded cellular prion protein (PrP^C), causing fatal neurodegenerative diseases in mammals. Species-specific amino acid substitutions (AAS) arising from single nucleotide polymorphisms within the prion protein gene (<i>Prnp</i>) modulate prion disease pathogenesis, and, in several instances, reduce susceptibility of homo- or heterozygous AAS carriers to prion infection. However, a mechanistic understanding of their protective effects against clinical disease is missing. We generated gene-targeted mouse infection models of chronic wasting disease (CWD), a highly contagious prion disease of cervids. These mice express wild-type deer or PrP^C harboring the S138N substitution homo- or heterozygously, a polymorphism found exclusively in reindeer (<i>Rangifer tarandus spp.</i>) and fallow deer (<i>Dama dama</i>). The wild-type deer PrP-expressing model recapitulated CWD pathogenesis including fecal shedding. Encoding at least one 138N allele prevented clinical CWD, accumulation of protease-resistant PrP (PrP^res) and abnormal PrP deposits in the brain tissue. However, prion seeding activity was detected in spleens, brains, and feces of these mice, suggesting subclinical infection accompanied by prion shedding. 138N-PrP^C was less efficiently converted to PrP^res in vitro than wild-type deer (138SS) PrP^C. Heterozygous coexpression of wild-type deer and 138N-PrP^C resulted in dominant-negative inhibition and progressively diminished prion conversion over serial rounds of protein misfolding cyclic amplification. Our study indicates that heterozygosity at a polymorphic <i>Prnp</i> codon can confer the highest protection against clinical CWD and highlights the potential role of subclinical carriers in CWD transmission.