Genetic and Pathological Follow-Up Study of Goats Experimentally and Naturally Exposed to a Sheep Scrapie Isolate

Abstract

Thirty-seven goats carrying different prion protein genotypes (PRNP) were orally infected with a classical scrapie brain homogenate from wild-type (ARQ/ARQ) sheep and then mated to obtain 2 additional generations of offspring, which were kept in the same environment and allowed to be naturally exposed to scrapie. Occurrence of clinical or subclinical scrapie was observed in the experimentally infected goats (F 0 ) and in only one (F 1b ) of the naturally exposed offspring groups. In both groups (F 0 and F 1b ), goats carrying the R154H, H154H, R211Q, and P168Q-P240P dimorphisms died of scrapie after a longer incubation period than wild-type, G37V, Q168Q-P240P, and S240P goats. In contrast, D145D and Q222K goats were resistant to infection. The immunobiochemical signature of the scrapie isolate and its pathological aspects observed in the sheep donors were substantially maintained over 2 goat generations, i.e., after experimental and natural transmission. This demonstrates that the prion protein gene sequence, which is shared by sheep and goats, is more powerful than any possible but unknown species-related factors in determining scrapie phenotypes. With regard to genetics, our study confirms that the K222 mutation protects goats even against ovine scrapie isolates, and for the first time, a possible association of D145 mutation with scrapie resistance is shown. In addition, it is possible that the sole diverse frequencies of these genetic variants might, at least in part, shape the prevalence of scrapie among naturally exposed progenies in affected herds. IMPORTANCEThis study was aimed at investigating the genetic and pathological features characterizing sheep-to-goat transmission of scrapie. We show that in goats with different prion protein gene mutations, the K222 genetic variant is associated with scrapie resistance after natural and experimental exposure to ovine prion infectivity. In addition, we observed for the first time a protective effect of the D145 goat variant against scrapie. Importantly, our results demonstrate that the phenotypic characteristic of the wild-type sheep scrapie isolate is substantially preserved in goats carrying different susceptible PRNP gene variants, thus indicating that the prion protein gene sequence, which is shared by sheep and goats, plays a fundamental role in determining scrapie phenotypes.

Genetic resistance to transmissible spongiform encephalopathies (TSE) in goats

“…According to Hardy–Weinberg equilibrium calculations, homozygotes for one rare allele (< 5%) will have a frequency of less than 0.3%, while heterozygotes for two rare alleles will have a frequency of less than 0.5%. The published surveys with full genotype information confirm the expected low frequencies: all homozygotes (excluding wild‐type alleles) were 0.48% and all double heterozygotes (no wild‐type alleles) were 0.43% (based on a total of almost 2600 genotypes) (Billinis et al., ; Acutis et al., ; Vaccari et al., ; Papasavva‐Stylianou et al., ; Bouzalas et al., ; Fragkiadaki et al., ; Goldmann et al., , ; Papasavva‐Stylianou et al., ; Maestrale et al., ; Acín et al., Corbière et al., ; Barillet et al., ). Despite the overall problem with assigning resistance to rare homozygotes due to their observed frequencies, a protective phenotype has been described for MM142 homozygotes similar to IM142 heterozygotes (Table ) (González et al., ; Goldmann et al., ) and also for SS146 and DD146 homozygotes compared to NS146 and ND146 heterozygotes (Georgiadou et al., ).…”

“…(Cyprus, 2015), HR154 (i.c., p.o.) (Lacroux et al., ; Maestrale et al., ), QR211 (i.c., p.o.) (Lacroux et al., ; Maestrale et al., ); and QK222 (i.c., p.o.)…”

“…(Lacroux et al., ; Maestrale et al., ), QR211 (i.c., p.o.) (Lacroux et al., ; Maestrale et al., ); and QK222 (i.c., p.o.) (Acutis et al., ; White et al., ; Lacroux et al., ; Maestrale et al., ) and in five homozygous genotypes: DD145 (p.o.)…”

“…(Lacroux et al., ; Maestrale et al., ); and QK222 (i.c., p.o.) (Acutis et al., ; White et al., ; Lacroux et al., ; Maestrale et al., ) and in five homozygous genotypes: DD145 (p.o.) (Maestrale et al., ), QQ211 (i.c.)…”

Controlling scrapie and bovine spongiform encephalopathy in goats

“…Some allelic variations in the PRNP gene could potentially protect species against the disease, or at least extend the incubation period. Those identified are: S/G127, I/M142, G/D145, H/R143, N/S146, N/D146, R/H154, R/Q211 and Q/K222 (Goldmann and others 1996, 2011, Billinis and others 2002, Acutis and others 2006, Vaccari and others 2006, 2009, Papasavva-Stylianou and others 2007, 2011, Barillet and others 2009, Gonzalez and others 2009, Serrano and others 2009, Bouzalas and others 2010, Hussain and others 2011, Acin and others 2013, Corbiere and others 2013, Maestrale and others 2015). …”