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

基本信息

批准号：
10185649
负责人：
Glenn C Telling
金额：
$ 51.36万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10185649
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 Farming environment 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 Structure 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

项目摘要

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发展的环境对人类造成的风险朊病毒，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潜力的鹿科动物。了解新出现的 CWD 菌株的特性、它们的起源、如何它们会适应和进化，它们的人畜共患威胁是重要的目标。我们提出四个具体目标来解决宿主朊病毒蛋白 (PrPC) 的构象转变和所得产物的适应性选择的假设感染性构象异构体 (PrPSc) 受到 PrP 残基 226（单一一级结构）变异的影响易感鹿科物种之间 PrP 的差异。由于我们进一步提出非 CNS 中的菌株选择隔室影响 CWD 传播，我们扩大使用基因靶向 (Gt) 策略以实现准确生理性 PrP 表达是该提案的关键组成部分。目标我将描述的属性新出现的 CWD 菌株。我们的策略建立在证据之上，表明朊病毒菌株正在推动当前的北方美国CWD流行病是由不稳定的新毒株演变而来。 Aim II 将通过以下方式探索 CWD 的起源：解决非典型菌株起源于同域物种中朊病毒暴露的假设，或来自鹿 PrPC 的随机自发转化。我们预计迭代传代和适应将产生具有与已建立的 CWD 一致的特性的菌株。目标 III 将探讨准确的提案 Gt 小鼠中的生理性 PrP 表达使它们特别适合研究品系适应。我们期望不同的接种途径会选择不同的菌株，并且外周血中CWD朊病毒的特性隔室与中枢神经系统中的隔室不同。我们展示了新出现的菌株及其已证实的适应潜力增加了 CWD 人畜共患疾病的不确定性。在目标 IV 中，我们新聘用了表达人类 PrP 的优化 Gt 小鼠，我们期望这将为探索人类提供改进的应用朊病毒病发病机制，以及评估人畜共患病 CWD 传播潜力的准确方法。我们的研究结果将有助于对抗慢性疾病的无法治愈的致命性和不可预测的流行病和人畜共患潜力通过了解朊病毒的繁殖方式以及作为可遗传菌株与多变的宿主存在来识别朊病毒在选择压力下适应和发展的范围属性。