Espinosa Juan Carlos, Fernández-Borges Natalia, Marín-Moreno Alba, Canoyra Sara, Aguilar-Calvo Patricia, Pintado Belén, Pericuesta Eva, Benestad Sylvie L, Nonno Romolo, Andréoletti Olivier, Torres Juan María
Biología Molecular y Celular de Priones, Centro de Investigación en Sanidad Animal, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria-Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Transgenesis Facility, Centro Nacional de Biotecnología-Universidad Autónoma de Madrid, Madrid, Spain.
J Infect Dis. 2025 Jul 30;232(1):e89-e98. doi: 10.1093/infdis/jiaf170.
Classical scrapie in sheep is caused by several different strains rather than a single strain, as is the case for epidemic classical bovine spongiform encephalopathy (BSE). Polymorphisms R171 and K176 located in the β2-α2 loop region of sheep prion protein (PrP) have been associated with potential protection for the propagation of classical scrapie.
The protective role of R171 and K176 polymorphic variants in susceptibility and resistance to different prion strains circulating in Europe was investigated using transgenic mouse lines expressing R171 or K176 sheep PrP in comparable levels (R171-Tg552 and K176-Tg570, respectively). Both lines were intracranially challenged with a panel of isolates representative of diverse prion strains, including at least 4 different classical scrapie strains. These isolates were previously characterized by transmission studies in ovine (Wt-OvPrP-Tg501) and bovine (BoPrP-Tg110) transgenic mice.
R171-Tg552 and K176-Tg570 mouse lines succumbed after the inoculation of atypical scrapie isolates with 100% attack rates and long survival times. However, the propagation of all tested classical scrapie isolated was completely blocked in R171-Tg552 mice, whereas in K176-Tg570 mice the propagation of most of the classical scrapie isolates was highly restricted or completely blocked depending on the prion strain. BSE transmission to R171-Tg552 mice was only possible after its adaptation to sheep PrP while no infection could be detected in K176-Tg570 mice, even after passage in sheep.
These results indicate that the R171 and K176 polymorphic variants of the ovine PrP sequence restrict the propagation of prions in a strain-dependent manner and are useful tools for prion strain discrimination.
绵羊的经典痒病是由几种不同毒株引起的，而非像流行性经典牛海绵状脑病（BSE）那样由单一毒株引起。绵羊朊病毒蛋白（PrP）β2-α2环区域中的R171和K176多态性与经典痒病传播的潜在保护作用相关。
使用以可比水平表达R171或K176绵羊PrP的转基因小鼠品系（分别为R171-Tg552和K176-Tg570），研究R171和K176多态性变体在欧洲流行的不同朊病毒毒株易感性和抗性中的保护作用。两个品系均经颅内接种一组代表不同朊病毒毒株的分离株，包括至少4种不同的经典痒病毒株。这些分离株先前已通过在绵羊（野生型绵羊PrP-Tg501）和牛（牛PrP-Tg110）转基因小鼠中的传播研究进行了表征。
接种非典型痒病分离株后，R171-Tg552和K176-Tg570小鼠品系全部感染，攻击率为100%，存活时间长。然而，所有测试的经典痒病分离株的传播在R171-Tg552小鼠中完全受阻，而在K176-Tg570小鼠中，大多数经典痒病分离株的传播根据朊病毒毒株的不同受到高度限制或完全受阻。BSE向R171-Tg552小鼠的传播只有在其适应绵羊PrP后才有可能，而在K176-Tg570小鼠中即使在绵羊中传代后也未检测到感染。
这些结果表明，绵羊PrP序列的R171和K176多态性变体以毒株依赖性方式限制朊病毒的传播，是区分朊病毒毒株的有用工具。
