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

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 朊病毒，特别是那些导致慢性消耗病（CWD），一种无法控制的传染性流行病， 不确定的人畜共患的鹿科动物。了解新出现的慢性消耗病菌株的特性，它们的起源， 它们适应和进化，它们的人畜共患病威胁是重要目标。我们提出了四个具体目标，以解决 宿主朊病毒蛋白（PrPC）的构象转换和产生的适应性选择 感染性构象异构体（PrPSc）受PrP残基226（单一一级结构）变异的影响 敏感鹿科动物之间PrP的差异。由于我们进一步提出，非中枢神经系统中的菌株选择 隔室影响CWD的传播，我们扩大使用基因靶向（Gt）策略， 生理PrP表达是该提议的关键组成部分。目的我将表征的性质， CWD紧急应变。我们的策略建立在证据的基础上，证据表明朊病毒株驱动了目前的北方 美国慢性消耗病的流行是由不稳定的新发毒株演变而来的。目的II将探讨慢性消耗病的起源， 解决了非典型菌株起源于同域物种中朊病毒暴露的假设， 由鹿朊病毒的随机自发转化引起的我们希望迭代传代和适应将 导致菌株的特性与已建立的CWD一致。目标三将探讨准确的建议， 在Gt小鼠中的生理PrP表达使它们独特地适合于研究品系适应。我们预计 不同的接种途径将选择不同的菌株，并且CWD朊病毒的性质在外周血中 这些区域与CNS中的区域不同。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。在目标四，我们雇用新的 我们期望表达人PrP的优化的Gt小鼠将提供改进的应用以探索人PrP。 朊病毒病的发病机制，以及评估人畜共患慢性消耗病传播潜力的准确方法。我们 研究结果将有助于对抗慢性消耗病的不可治愈的致命性和不可预测的流行病和人畜共患病潜力 朊病毒通过了解他们的方式繁殖和存在的遗传菌株与千变万化的主机 在选择性压力下适应和进化的范围特性。

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.