Abstract:
While animal prion diseases are a threat to human health, their zoonotic potential is generally inefficient because of interspecies prion transmission barriers. New animal models are required to provide an understanding of these prion transmission barriers and to assess the zoonotic potential of animal prion diseases. To address this goal, we generated Drosophila transgenic for human or nonhuman primate prion protein (PrP) and determined their susceptibility to known pathogenic prion diseases, namely varient Creutzfeldt-Jakob disease (vCJD) and classical bovine spongiform encephalopathy (BSE), and that with unknown pathogenic potential, namely chronic wasting disease (CWD). Adult Drosophila transgenic for M129 or V129 human PrP or nonhuman primate PrP developed a neurotoxic phenotype and showed an accelerated loss of survival after exposure to vCJD, classical BSE, or CWD prions at the larval stage. vCJD prion strain identity was retained after passage in both M129 and V129 human PrP Drosophila. All of the primate PrP fly lines accumulated prion seeding activity and concomitantly developed a neurotoxic phenotype, generally including accelerated loss of survival, after exposure to CWD prions derived from different cervid species, including North American white-tailed deer and muntjac, and European reindeer and moose. These novel studies show that primate PrP transgenic Drosophila lack known prion transmission barriers since, in mammalian hosts, V129 human PrP is associated with severe resistance to classical BSE prions, while both human and cynomolgus macaque PrP are associated with resistance to CWD prions. Significantly, our data suggest that interspecies differences in the amino acid sequence of PrP may not be a principal determinant of the prion transmission barrier.
摘要:
虽然动物朊病毒疾病对人类健康构成威胁,由于种间朊病毒传播障碍,它们的人畜共患潜力通常是低效的。需要新的动物模型来提供对这些朊病毒传播障碍的理解,并评估动物朊病毒疾病的人畜共患潜力。为了实现这一目标,我们为人类或非人类灵长类PrP产生了果蝇转基因,并确定了它们对已知致病性病毒疾病的易感性,即vCJD和经典疯牛病,并且具有未知的致病潜力,即CWD。M129或V129人类PrP的成年果蝇转基因,或非人类灵长类PrP出现了神经毒性表型,并在暴露于vCJD后表现出加速的存活丧失,经典疯牛病,或幼虫期的CWD病毒。在M129和V129人PrP果蝇中传代后,vCJD朊病毒株的身份得以保留。所有灵长类PrP蝇系都积累了朊病毒播种活性,并伴随发展出神经毒性表型,通常包括加速的生存损失,暴露于来自不同子宫颈物种的CWD病毒后,包括北美白尾鹿和muntjac,还有欧洲驯鹿和驼鹿.这些新的研究表明,灵长类PrP转基因果蝇缺乏已知的朊病毒传播障碍,在哺乳动物宿主中,V129人类PrP与对经典疯牛病病毒的严重抗性有关,而人类和食蟹猴PrP都与对CWD病毒的抗性有关。重要的是,我们的数据表明,PrP氨基酸序列的种间差异可能不是朊病毒传播障碍的主要决定因素。