Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, 59840, USA.
Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, 59840, USA.
Acta Neuropathol. 2024 Oct 24;148(1):56. doi: 10.1007/s00401-024-02813-y.
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.
慢性消瘦病（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 和其他哺乳动物天然朊病毒病的传染性朊病毒结构仍知之甚少。在此，我们报道了一个分辨率为 2.8Å 的基于冷冻电子显微镜的 CWD 朊病毒纤丝结构，该纤丝来自表达最常见的野生型 PrP 序列的自然感染的白尾鹿的大脑。与最近解决的啮齿动物适应的瘙痒病朊病毒纤丝一样，我们的 CWD 纤丝原子模型包含单个 PrP 分子堆栈，这些分子堆栈形成平行的、有序的分子间β-折叠，并在纤丝横截面上包含主要的 N 端和 C 端结构域之间的间隔环。然而，天然鹿科宿主的 CWD 纤丝在许多其他特征上与啮齿动物结构明显不同，包括结构域相对取向的约 180°扭曲。该 CWD 结构表明了导致 CWD 向人类传播的明显障碍的机制，这应该有助于更合理地开发 CWD 疫苗和疗法。
