Mechanisms of prion spread and establishment of infection

朊病毒传播和感染建立的机制

基本信息

批准号：
10405453
负责人：
Jason C Bartz
金额：
$ 46.27万
依托单位：
CREIGHTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405453
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 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 detection method detection platform detection sensitivity experience illness length innovation prion hypothesis prophylactic retrograde transport sciatic nerve trafficking uptake

项目摘要

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.

病毒疾病不可避免地是致命的感染性神经退行性疾病，包括人类，没有已知的治愈方法。 prions主要（即使不是完全）的PRPSC，这是一种错误的形式正常的非感染prion蛋白PRPC。虽然王室如何进入神经系统的细节原因尚不清楚，目前的模型包括对淋巴组织（LRS），这些组织中的复制/积累，随后转运到中枢神经系统（CNS）。人们认为神经浸觉是通过支配LRS组织和副交感神经的交感神经发生的神经支配肠壁上的肠神经系统。我们小组和其他人的最新工作表明，与粘膜表面接触的王室在几分钟内传播到血液，可以是在疾病期间在血液中检测到。该priONEMIA在发病机理中的作用，包括尚未检查神经侵入。我们提供了循环系统界面的结构的证据神经系统可以支持Prion复制，并且可能是Prion神经入侵的重要门户。总体而言，关于初始建立感染，接种物和接种物的清除和是否需要复制神经入侵。这个重大问题受到了无法区分接种PRPSC与新形成的PRPSC。这些研究的长期目标是确定初始prion复制的部位并确定新的神经侵入途径。这个目的应用是在自然之后确定接种物prPSC的时间和空间扩散接种途径，以识别prion传播和神经入侵的途径。我们假设那个王子迅速传播到整个主机中，独立于代理复制。为了实现这一目标，我们开发了强大的动物系统和超敏感的prion检测技术最初吸收和prions传播中的重要发现。我们提出的创新方法没有需要在Trans中富集或标记PRPSC，并避免使用变化的PRPSC淀粉样蛋白和有限的伪像检测灵敏度。我们已经表明，prPSC或PRPSC与土壤交叉上皮，排水至淋巴系统并在口腔或外鼻外接种的几分钟内进入血液。我们还表明一次私人进入周围神经系统，它们沿着定义的神经解剖学逆转途径。最后，我们有数据表明淋巴酸性系统（LRS）复制缺陷prion 菌株沿已知的病毒途径运输，但无法确定疾病。使用这些新知识和我们确定幼虫是否导致王室的广泛传播，在没有的情况下 prion转化，随后是组织特异性衰减的速率。这些目标的结果将决定神经侵袭和透射性的早期发病机理中的早期事件传播。