Mechanisms of prion spread and establishment of infection

Pron病是动物不可避免的致命的传染性神经退行性疾病，包括 人类，没有已知的治疗方法。PrPSc是由PrPSc组成的，如果不是全部的话，PrPSc是PrPSc的一种错误折叠形式 正常的非传染性病毒蛋白PrPC。尽管有关普里恩如何进入神经系统和 致病原因尚不清楚目前的模型包括Pron向淋巴网状组织(LRs)的运输， 在这些组织中复制/积累，随后运输到中枢神经系统(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 肠壁中支配肠道神经系统的神经。我们小组和其他人最近的工作是 研究表明，与粘膜表面接触的普恩病毒在几分钟内就会传播到血液中，并可以 在疾病的持续时间内在血液中检测到。这种原蛋白血症在发病机制中的作用包括 神经侵袭，还没有被检查过。我们提供的证据表明，在循环系统交界处的结构 神经系统支持病毒复制，可能是病毒侵袭神经的重要途径。 总体而言，对最初建立感染的部位(S)、接种清除和 神经侵袭是否需要复制制剂。这一重大问题一直受到 无法区分接种的PrPSc和新形成的PrPSc。这些研究的长期目标是 确定最初的Prion复制的位置，并确定神经侵袭的新途径。这样做的目的是 应用是确定接种物PrPSc在自然条件下在宿主中的时空传播 确定病毒传播途径和神经侵袭途径的接种途径。我们假设普里恩 独立于代理复制在整个主机中快速传播。为了实现这一目标，我们有 开发了强大的动物系统和超灵敏的普恩检测技术，导致了 在普恩的最初吸收和传播方面的重要发现。我们提议的创新方法不会 要求在反式中浓缩或标记PrPSc，并避免PrPSc淀粉样蛋白状态改变和有限的伪影 检测灵敏度。我们已经证明了PrPSc或PrPSc结合到土壤上会穿过上皮细胞，排出到 淋巴系统，并在口服或鼻外接种后几分钟内进入血液。我们还表明，一旦 Pron进入周围神经系统，它们沿着定义的神经解剖学逆行运输 小路。最后，我们有数据表明，淋巴网状系统(LRS)复制缺陷的普恩 毒株沿着已知的普恩病毒途径传播，但无法建立疾病。利用这一新知识和 我们确定在没有普恩病毒的情况下，普恩蛋白血症是否会导致普恩蛋白的迅速广泛传播 Prion转换，紧随其后的是特定组织的衰减率。这些目标的结果将决定 Pron致病的早期事件以及神经侵袭和跨突触是否需要Pron转换 散开。

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.