Chronic wasting disease (CWD) is a widely distributed prion disease of cervids with implications for wildlife conservation and also for human and livestock health. The structures of infectious prions that cause CWD and other natural prion diseases of mammalian hosts have been poorly understood. Here we report a 2.8 Å resolution cryogenic electron microscopy-based structure of CWD prion fibrils from the brain of a naturally infected white-tailed deer expressing the most common wild-type PrP sequence. Like recently solved rodent-adapted scrapie prion fibrils, our atomic model of CWD fibrils contains single stacks of PrP molecules forming parallel in-register intermolecular β-sheets and intervening loops comprising major N- and C-terminal lobes within the fibril cross-section. However, CWD fibrils from a natural cervid host differ markedly from the rodent structures in many other features, including a ~ 180° twist in the relative orientation of the lobes. This CWD structure suggests mechanisms underlying the apparent CWD transmission barrier to humans and should facilitate more rational approaches to the development of CWD vaccines and therapeutics.

慢性消耗性疾病 （CWD） 是一种广泛分布的鹿科动物朊病毒病，对野生动物保护以及人类和牲畜健康都有影响。引起 CWD 和哺乳动物宿主的其他天然朊病毒病的传染性朊病毒的结构知之甚少。在这里，我们报道了来自自然感染的白尾鹿大脑的 CWD 朊病毒原纤维的 2.8 Å 分辨率低温电子显微镜结构，表达最常见的野生型 PrP 序列。与最近解决的啮齿动物适应的痒病朊病毒原纤维一样，我们的 CWD 原纤维原子模型包含单堆 PrP 分子，形成平行的寄存器内分子间 β 片和中间环，包括原纤维横截面内的主要 N 端和 C 端叶。然而，来自天然鹿科动物宿主的 CWD 原纤维在许多其他特征上与啮齿动物结构明显不同，包括裂片相对方向的 ~ 180° 扭曲。这种 CWD 结构表明了 CWD 向人类传播障碍的明显机制，应该有助于以更合理的方法开发 CWD 疫苗和治疗方法。