White-tailed deer S96 prion protein does not support stable in vitro propagation of most common CWD strains

PrP^C variation at residue 96 (G/S) plays an important role in the epidemiology of chronic wasting disease (CWD) in exposed white-tailed deer populations. In vivo studies have demonstrated the protective effect of serine at codon 96, which hinders the propagation of common CWD strains when expressed in homozygosis and increases the survival period of S96/wt heterozygous deer after challenge with CWD. Previous in vitro studies of the transmission barrier suggested that following a single amplification step, wt and S96 PrP^C were equally susceptible to misfolding when seeded with various CWD prions. When we performed serial prion amplification in vitro using S96-PrP^C, we observed a reduction in the efficiency of propagation with the Wisc-1 or CWD2 strains, suggesting these strains cannot stably template their conformations on this PrP^C once the primary sequence has changed after the first round of replication. Our data shows the S96-PrP^C polymorphism is detrimental to prion conversion of some CWD strains. These data suggests that deer homozygous for S96-PrP^C may not sustain prion transmission as compared to a deer expressing G96-PrP^C.