In Vivo Comparison of Chronic Wasting Disease Infectivity from Deer with Variation at Prion Protein Residue 96

Abstract

Chronic wasting disease (CWD) is a prion disease of cervids that causes neurodegeneration and death. Susceptibility to prion infections, including CWD, can be dependent on the amino acid sequence of the host prion protein (PrP). Here, CWD agent obtained from a deer expressing the 96SS genotype, associated with partial resistance to CWD, was used to infect transgenic (tg) mice expressing either 96GG or 96SS deer PrP. Transgenic mice expressing 96GG deer PrP succumbed to this agent, but tg mice expressing 96SS deer PrP did not. Additional studies using inocula from 96GG deer showed no transmission to 96SS PrP mice and delayed disease in 96GS mice. Thus, 96S PrP played an inhibitory role in disease progression in tg mice.Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) or prion disease of North American cervids that causes progressive neurodegeneration and death (24,26). Disease occurs when the normal (sensitive) host prion protein (PrPsen) is converted to an abnormal, diseaseassociated, protease-resistant form (PrPres). The incidence of CWD continues to increase in wild and captive cervids of North America, most likely via direct animal-to-animal contact or exposure to CWD agent-contaminated environments. It is known that the sequence of the host prion protein gene (PRNP) can affect susceptibility to TSE diseases, including scrapie in sheep (4) and laboratory mice (2), sporadic Creutzfeldt-Jakob disease (sCJD) (1, 6, 17), variant CJD (25) and kuru (11) in humans, and CWD in cervids (23). Susceptibility to the CWD agent has been shown to correlate with specific amino acids at defined locations within the PRNP gene, including codon 96 in white-tailed deer (9,12,15,27), codons 20 and 225 in mule deer (7,27), and codon 132 in elk (5). Approximately 55% of white-tailed deer are homozygous for glycine at position 96 (96GG), ϳ35% have glycine/serine at this position (96GS), and Յ10% are serine homozygotes (96SS), depending on geographic location (9,15,27). Strong evidence exists to show that both the 96GS and 96SS genotypes are underrepresented among populations of CWD agent-infected white-tailed deer (8,9,15,27). It is unclear if the low incidence of disease in 96GS and 96SS deer reflects only resistance to a particular CWD agent strain or is in fact a protective factor provided by cervid 96S prion protein.In some situations in which TSE occurs in an animal with a previously resistant genotype or a new species, agent adaptation and selection can occur with greater efficiency in the subsequent spread to additional individuals with similar genotypes (14, 19). By analogy, in cervids, PrPres from a few CWD agent-positive 96SS individuals might adapt to become more infectious for additional 96SS deer. To test this possibility, we developed transgenic (tg) mice that express various PRNP genotypes at codon 96 to model the situation in deer. Transgenic mice that express deer PrP with glycine at position 96 (96GG) (described previously as tg33 [12,18]) expressed PrPsen at levels comparable to the ...

Structural effects of PrP polymorphisms on intra- and interspecies prion transmission

“…Previous studies consistently showed Tg60 mice expressing deer PrP-S96 to be entirely resistant to CWD, and investigators were unable to identify PrP Sc in the brains of asymptomatic Tg60 mice (26,27). Our results show that after long incubation times CWD-infected Tg(DeerPrP-S96)7511 +/− mice were ultimately susceptible to disease, albeit with incomplete attack rates.…”

Pathways of Prion Spread during Early Chronic Wasting Disease in Deer

“…Of these polymorphisms, Q95, G96, and A116 are more common in the deer population and reported with higher frequency in natural cases of CWD (18). Studies have demonstrated at least one copy of the S96 allelic variation prolongs the CWD incubation period in deer, up to 230%, and appears to impede but not prevent PrP CWD conversion (2,19,20).…”

Survival Patterns in White-tailed and Mule Deer after Oral Inoculation with a Standardized, Conspecific Prion Dose

“…CWD accumulation and prolonged survival (and perhaps partial resistance to natural infection) associated with the glycine to serine change at position 96 of the white-tailed deer PRNP gene (Johnson et al, 2006(Johnson et al, , 2011Meade-White et al, 2007;Race et al, 2011) is similar to the influences of a serine to phenylalanine change at PRNP position 225 on PrP CWD accumulation and survival in mule deer (Fox et al, 2006). Variation among white-tailed deer sampled here should afford opportunities to evaluate genetic influences on agent shedding once appropriate tools have been developed.…”

“…Samples collected during this study were shared with at least five other institutions, and some of these collaborations have helped advance scientific understanding of CWD and prion diseases in general (Chang et al, 2007;Wolfe et al, 2007;Tamgü ney et al, 2009Tamgü ney et al, , 2012Race et al, 2011;Rubenstein et al, 2011). Other studies are under way using materials arising from our work, and additional endeavors will be supported as feasible.…”