Addressing the mechanisms of prion strain evolution and its effect on interspecies transmission

解决朊病毒株进化的机制及其对种间传播的影响

• 批准号: 10378707
• 负责人: Glenn C Telling
• 金额: $ 47.69万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378707
• 关键词: Address; American; Animal Diseases; Animals; Automobile Driving; Cattle; Characteristics; Chronic Wasting Disease; Deer; Disease; Disease Outcome; Economics; Epidemic; European; Event; Evolution; Exhibits; Exposure to; Farm; Gene Targeting; Genetic Polymorphism; Genotype; Glutamine; Goals; Heritability; Human; Hybrids; Lead; Location; Lymphoid Tissue; Mink; Modeling; Molecular; Molecular Conformation; Mus; Muscle; Nerve Degeneration; North America; Outcome; Pathogenesis; Peripheral; Physiological; Population; Positioning Attribute; PrP; PrPSc Proteins; Predisposition; Prion Diseases; Prions; Property; Proteins; Rest; Risk Management; Role; Route; Scrapie; Sheep; Skeletal Muscle; Transgenic Organisms; Uncertainty; Variant; Virus; Zoonoses; base; cervid; conformational conversion; conformer; cross-species transmission; disease transmission; human PrP; improved; in vitro Model; innovation; mouse model; novel; pressure; response; tissue tropism; transmission process

Our broad, long-term objectives are to assess and manage the risk posed to humans from continually evolving prions, specifically those causing chronic wasting disease (CWD), an uncontrollable contagious epidemic of cervids of uncertain zoonotic potential. Understanding the properties of emergent CWD strains, their origins, how they adapt and evolve, and their zoonotic threats are important goals. We propose four Specific Aims to address the hypothesis that conformational conversion of host prion protein (PrPC) and adaptive selection of the resulting infectious conformers (PrPSc) is influenced by variation at PrP residue 226, the singular primary structural difference in PrP among susceptible cervid species. Since we further propose that strain selection in non-CNS compartments influences CWD transmission, our expanded use of gene targeting (Gt) strategies for accurate physiological PrP expression is a key component of this proposal. Aim I will characterize the properties of emergent CWD strains. Our strategy builds upon evidence indicating that prion strains driving the current North American CWD epidemic evolved from unstable emergent strains. Aim II will explore the origins of CWD by addressing the hypothesis that atypical strains originated either from exposure to prions in sympatric species, or from stochastic spontaneous conversion of cervid PrPC. We expect that iterative passaging and adaptation will result in strains with properties consistent with established CWD. Aim III will explore the proposal that accurate physiological PrP expression in Gt mice makes them uniquely suited to study strain adaptation. We expect that different inoculation routes will select different strains, and that the properties of CWD prions in peripheral compartments are different to those in the CNS. Our demonstration of novel emergent strains and their demonstrated potential for adaptation increases uncertainties about CWD zoonosis. In Aim IV we employ newly optimized Gt mice expressing human PrP that we expect will provide an improved application to explore human prion disease pathogenesis, and an accurate means to assess the potential for zoonotic CWD transmission. Our findings will aid in combating the incurable lethality and unpredictable epidemic and zoonotic potential of CWD prions by understanding the means by which they propagate and exist as heritable strains with protean host range properties that adapt and evolve under selective pressure.

我们广泛的长期目标是评估和管理不断进化给人类带来的风险 Prion，特别是那些导致慢性消耗性疾病(CWD)的病毒，这是一种无法控制的传染性流行病 具有不确定的人畜共患病潜力的鹿群。了解CWD新发菌株的特性、来源、方式 他们适应和进化，他们的人畜共患病威胁是重要的目标。我们提出了四个具体目标来解决 宿主蛋白(PrPC)的构象转换及其适应性选择假说 感染性构象(PrPSc)受PrP残基226位变异的影响，PrP残基是一种单一的一级结构 不同敏感鹿种间PrP的差异。由于我们进一步提出在非中枢神经系统中进行菌株选择 间隔影响CWD的传播，我们扩大使用基因靶向(GT)策略以准确 生理性PrP的表达是这一提议的关键组成部分。Aim我将描述它的特性 新出现的CWD菌株。我们的战略建立在证据的基础上，这些证据表明，推动当前北方 美国的CWD疫情是从不稳定的新发毒株进化而来的。AIM II将通过以下方式探索CWD的起源 解决了非典型菌株起源于共生物种中的普恩病毒的假设，或者 来自Cervid PrPC的随机自发转换。我们预计迭代传递和适应将 结果得到的菌株具有与已建立的CWD一致的特性。AIM III将探讨准确的建议 GT小鼠的生理性PrP表达使其特别适合于研究品系适应。我们期待着 不同的接种途径会选择不同的菌株，CWD外周病毒的特性 舱室不同于中枢神经系统的舱室。我们展示了新出现的菌株及其 已证明的适应潜力增加了CWD人畜共患病的不确定性。在AIM IV中，我们新雇用了 我们期望优化的表达人PrP的GT小鼠将为探索人类提供一个更好的应用 Prion病的发病机制，以及评估人畜共患病传播潜力的准确手段。我们的 这些发现将有助于抗击CWD的不可治愈的致命性、不可预测的流行病和人畜共患病的可能性。 通过了解它们的繁殖方式和作为可遗传菌株与多变宿主共存的方式 在选择压力下适应和发展的范围属性。