Mechanisms of prion spread and establishment of infection

朊病毒传播和感染建立的机制

• 批准号: 9917827
• 负责人: Jason C Bartz
• 金额: $ 49.55万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917827
• 关键词: Amyloid; Animal Model; Animals; Axon; Axonal Transport; Biological Assay; Blood; Brain; Cardiovascular system; Cells; Characteristics; Data; Detection; Disease; Enteric Nervous System; Epithelial; Epithelium; Event; Goals; Human; Infection; Knowledge; Label; Lumbar spinal cord structure; Lymphatic System; Mesocricetus auratus; Modeling; Morphologic artifacts; Motor Neurons; Mucous Membrane; Mus; Nerve; Nerve Degeneration; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neurons; Oral; Pathogenesis; Pathway interactions; Peripheral Nervous System; Positioning Attribute; PrP; PrPC Proteins; PrPSc Proteins; Prion Diseases; Prion Pathway; Prions; Red nucleus structure; Research Personnel; Role; Route; Site; Soil; Structure; Surface; Synapses; System; Techniques; Testing; Time; Tissues; Work; Zoonoses; cross-species transmission; experience; illness length; innovation; prion hypothesis; prophylactic; retrograde transport; sciatic nerve; trafficking; uptake

Prion diseases are inevitably fatal infectious neurodegenerative zoonotic disorders of animals, including humans, with no known cure. Prions are comprised largely, if not entirely, of PrPSc, a misfolded form of the normal non-infectious prion protein PrPC. Although the details of how prions enter the nervous system and cause disease are not known the current model consists of prion trafficking to lymphoreticular tissues (LRS), replication/accumulation in these tissues and subsequent transport into the central nervous system (CNS). Neuroinvasion is thought to occur via sympathetic nerves that innervate LRS tissue and parasympathetic nerves that innervate the enteric nervous system in the gut wall. Recent work from our group and others has shown that prions that come into contact with mucosal surfaces spread to blood within minutes and can be detected in blood for the duration of disease. The role of this prionemia in pathogenesis, including neuroinvasion, has not been examined. We provide evidence that structures at the interface of the circulatory and nervous system can support prion replication and may be important portals of prion neuroinvasion. Overall, very little is known about the site(s) of initial establishment of infection, clearance of inoculum and whether replication of agent is required for neuroinvasion. This significant problem has been hampered by the inability to differentiate inoculum PrPSc vs. newly formed PrPSc. The long-term goal of these studies is to identify the sites of initial prion replication and to identify new routes of neuroinvasion. The objective of this application is to determine the temporal and spatial spread of inoculum PrPSc in the host following natural routes of inoculation to identify the pathways of prion spread and neuroinvasion. We hypothesize that prions rapidly spread throughout the host independent of agent replication. To accomplish this objective we have developed powerful animal systems and ultrasensitive prion detection techniques that have resulted in important findings in the initial uptake and spread of prions. Our proposed innovative approach does not require enrichment or labeling of PrPSc in trans, and avoids artifacts of altered PrPSc amyloid state and limited detection sensitivity. We have shown that PrPSc or PrPSc bound to soil crosses epithelia, drains to the lymphatic system and enters blood within minutes of oral or extranasal inoculation. We also show that once prions enter the peripheral nervous system they are retrogradely transported along defined neuroanatomical pathways. Finally, we have data indicating that a lymphoreticular system (LRS) replication-deficient prion strain is transported along known prion pathways but fails to establish disease. Using this new knowledge and techniques we determine if prionemia results in rapid widespread dissemination of prions, in the absence of prion conversion, which is followed by a tissue-specific rate of decay. The results of these aims will determine the early events in prion pathogenesis and if prion conversion is required for neuroinvasion and transynaptic spread.

朊病毒病是动物不可避免的致命传染性神经退行性人畜共患疾病，包括 人类，没有已知的治疗方法。朊病毒主要（如果不是全部）由 PrPSc 组成，PrPSc 是蛋白质的错误折叠形式。 正常非感染性朊病毒蛋白PrPC。尽管朊病毒如何进入神经系统的细节 导致疾病的原因尚不清楚，目前的模型包括朊病毒转运至淋巴网状组织（LRS）， 在这些组织中复制/积累，然后转运到中枢神经系统 (CNS)。 神经侵袭被认为是通过支配 LRS 组织和副交感神经的交感神经发生的。 支配肠壁肠神经系统的神经。我们小组和其他人最近的工作 研究表明，与粘膜表面接触的朊病毒会在几分钟内扩散到血液中，并且可以被 在疾病期间在血液中检测到。这种朊病毒血症在发病机制中的作用，包括 神经侵犯，尚未检查。我们提供的证据表明循环界面的结构 神经系统可支持朊病毒复制，可能是朊病毒神经侵袭的重要门户。 总体而言，人们对最初感染的部位、接种物的清除和感染知之甚少。 神经侵袭是否需要药剂的复制。这个重大问题受到了阻碍 无法区分接种物 PrPSc 与新形成的 PrPSc。这些研究的长期目标是 确定最初的朊病毒复制位点并确定新的神经侵袭途​​径。此举的目的 应用程序是为了确定接种物 PrPSc 在自然环境下在宿主中的时间和空间传播 接种途径以确定朊病毒传播和神经侵袭的途径。我们假设朊病毒 独立于代理复制而在整个主机中快速传播。为了实现这个目标，我们有 开发了强大的动物系统和超灵敏的朊病毒检测技术，导致 朊病毒最初摄取和传播的重要发现。我们提出的创新方法并不 需要反式富集或标记 PrPSc，并避免改变 PrPSc 淀粉样蛋白状态和有限的伪影 检测灵敏度。我们已经证明，与土壤结合的 PrPSc 或 PrPSc 穿过上皮细胞，排出到土壤 口服或鼻外接种后几分钟内进入淋巴系统并进入血液。我们还表明，一旦 朊病毒进入周围神经系统，它们沿着定义的神经解剖学逆行运输 途径。最后，我们有数据表明淋巴网状系统（LRS）复制缺陷型朊病毒 菌株沿着已知的朊病毒途径运输，但未能形成疾病。利用这些新知识和 我们确定朊病毒血症是否会导致朊病毒快速广泛传播的技术，在没有 朊病毒转化，随后是组织特异性的腐烂率。这些目标的结果将决定 朊病毒发病机制的早期事件以及神经侵袭和突触是否需要朊病毒转化 传播。