Role of the Goat K ₂₂₂ -PrP ^C Polymorphic Variant in Prion Infection Resistance

Abstract

The prion protein-encoding gene (prnp) strongly influences the susceptibility of small ruminants to transmissible spongiform encephalopathies (TSEs). Hence, selective breeding programs have been implemented to increase sheep resistance to scrapie. For goats, epidemiological and experimental studies have provided some association between certain polymorphisms of the cellular prion protein (PrP C ) and resistance to TSEs. Among them, the Q/K polymorphism at PrP C codon 222 (Q/K 222 ) yielded the most promising results. In this work, we investigated the individual effects of the K 222 -PrP C variant on the resistance/susceptibility of goats to TSEs. For that purpose, we generated two transgenic mouse lines, expressing either the Q 222 (wild type) or K 222 variant of goat PrP C . Both mouse lines were challenged intracerebrally with a panel of TSE isolates. Transgenic mice expressing the wildtype (Q 222 ) allele were fully susceptible to infection with all tested isolates, whereas transgenic mice expressing similar levels of the K 222 allele were resistant to all goat scrapie and cattle BSE isolates but not to goat BSE isolates. Finally, heterozygous K/Q 222 mice displayed a reduced susceptibility to the tested panel of scrapie isolates. These results demonstrate a highly protective effect of the K 222 variant against a broad panel of different prion isolates and further reinforce the argument supporting the use of this variant in breeding programs to control TSEs in goat herds. IMPORTANCEThe objective of this study was to determine the role of the K 222 variant of the prion protein (PrP) in the susceptibility/resistance of goats to transmissible spongiform encephalopathies (TSEs). Results showed that transgenic mice expressing the goat K 222 -PrP polymorphic variant are resistant to scrapie and bovine spongiform encephalopathy (BSE) agents. This protective effect was also observed in heterozygous Q/K 222 animals. Therefore, the single amino acid exchange from Q to K at codon 222 of the cellular prion protein provides resistance against TSEs. All the results presented here support the view that the K 222 polymorphic variant is a good candidate for selective breeding programs to control and eradicate scrapie in goat herds.

Caprine PrP variants harboring Asp-146, His-154 and Gln-211 alleles display reduced convertibility upon interaction with pathogenic murine prion protein in scrapie infected cells

“…Recently published data on transgenic mice harboring the caprine Lys-222 allele after challenge with goat-scrapie and other TSE isolates, assigned strong protection to this allele. 25 Similarly, studies on experimental transmission (oral 28 or intracerebral 27 ) of natural goat scrapie isolates in heterozygous Lys-222 goats, concluded that Lys-222 significantly extends survival time after inoculation, 28 with no signs of PrP SC deposition up to 4,5 y post-inoculation. 27 Further, protective effects were assigned to the His-154, Gln-211 and Lys-222 alleles after oral or intracerebral inoculation of goats (wild type, heterozygous or homozygous for each of these alleles) with a single naturally occurring goat scrapie isolate.…”

“…11,[21][22][23] These alleles' relative low occurrence frequency among herds and/or goat breeds examined in field studies, suggests that additional investigations within the context of a well defined experimental scheme, including sufficient test samples and controls, are required prior to gaining further conclusive information on their effects. Different experimental approaches, utilizing either in vitro 24 or in vivo [25][26][27][28] methodologies, have been used toward this direction.…”

“…The in vitro approach utilized a cellfree system to estimate the conversion potential of several alleles. 24 In parallel, in vivo studies were initialized on either transgenic mice harboring caprine Prnp alleles, 25 or on experimentally challenged goats carrying the genotypes of interest. [26][27][28] In the present work we report the in vitro study of murine-caprine PrP chimeras consisting of the mature caprine Prnp sequence and carrying the alleles of interest, in a murine cell model of scrapie.…”

Review: A review on classical and atypical scrapie in caprine: Prion protein gene polymorphisms and their role in the disease

“…Susceptibility or resistance to scrapie varies among sheep and goats depending on the PrP genotype of the host and the infectious strain (Hunter, 1997;Agrimi et al, 2003;Baylis and Goldmann, 2004;Aguzzi et al, 2007;Aguilar-Calvo et al, 2014). In many countries, scrapie represents a relevant cause of mortality in ewes, but, by itself, is not a hazard to humans.…”

“…It could be useful to develop a genetic selection plan to eradicate and control the disease (White et al, 2012;Fast and Groschup, 2013;Aguilar-Calvo et al, 2014 andLacroux et al, 2014).…”