Key Molecular Mechanisms of TSEs

TSE 的关键分子机制

• 批准号: 9211114
• 负责人: MARK D ZABEL
• 金额: $ 37.19万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-16 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9211114
• 关键词: Affect; Agriculture; Animals; Antigens; Area; B-Lymphocytes; Binding; Blood; Blood Donations; Bovine Spongiform Encephalopathy; Brain; Canada; Cattle; Cessation of life; Chronic Wasting Disease; Cleaved cell; Complement; Complement 1q; Complement 3d Receptors; Complement Activation; Complement Receptor; Consensus; Creutzfeldt-Jakob Syndrome; Data; Disease Outbreaks; Emotions; Enzyme Precursors; Epidemic; Europe; Exhibits; Farming environment; Follicular Dendritic Cells; Funding; Health; Human; Image; Immune system; Infection; Infectious Agent; Inflammatory; Invaded; Life; Lymphoid Follicle; Mediating; Modeling; Molecular; Monitor; Mouse Strains; Mus; Neurodegenerative Disorders; North America; Nucleic Acids; Opsonin; Organ; Organ Donations; Pathogenesis; Peripheral; Play; Population; PrPCWD; PrPSc Proteins; Prion Diseases; Prions; Process; Public Health; Reporting; Research; Research Personnel; Role; Scrapie; Serum; Sheep; Spleen; Surveys; Terminal Disease; Testing; Time; Tissues; Tropism; United States National Institutes of Health; Variant; Work; Zoonoses; adaptive immunity; cervid; complement system; density; extracellular; in vivo; innovation; microbial; novel; pathogen; preference; relating to nervous system; trafficking; transmission process; vigilance

 DESCRIPTION (provided by applicant): Prion diseases, or transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative diseases affecting humans, cervids, bovids, and ovids. The absolute requirement of PrPC expression to generate prion diseases and the lack of instructional nucleic acid define prions as unique infectious agents. Prions exhibit species-specific tropism, inferring that unique prion strains exist that preferentially infct certain host species and confront transmission barriers to heterologous host species. However, transmission barriers are not absolute. Scientific consensus agrees that the sheep TSE scrapie probably breached the transmission barrier to cattle causing bovine spongiform encephalopathy that subsequently breached the human transmission barrier and likely caused several hundred deaths by a new-variant form of the human TSE Creutzfeldt-Jakob disease in the UK and Europe. The impact to human health, emotion and economies can still be felt in areas like farming, blood and organ donations and the threat of a latent TSE epidemic. This precedent raises the real possibility of other TSEs, like chronic wasting disease of cervids, overcoming similar human transmission barriers. A groundbreaking discovery made last year revealed that mice infected with heterologous prion strains facing significant transmission barriers replicated prions far more readily in spleens than brains6. Furthermore, these splenic prions exhibited weakened transmission barriers and expanded host ranges compared to neurogenic prions. These data question conventional wisdom of avoiding neural tissue to avoid prion xenotransmission, when more promiscuous prions may lurk in extraneural tissues. Data derived from work previously funded by NIH demonstrate that Complement receptors CD21/35 bind prions and high density PrPC and differentially impact prion disease depending on the prion isolate or strain used. Recent advances in live animal and whole organ imaging have led us to generate preliminary data to support novel, innovative approaches to assessing prion capture and transport. We plan to test our unifying hypothesis for this proposal that CD21/35 control the processes of peripheral prion capture, transport, strain selection and xenotransmission in the following specific aims. 1. Assess the role of CD21/35 in splenic prion strain selection and host range expansion. 2. Determine whether CD21/35 and C1q differentially bind distinct prion strains 3. Monitor the effects of CD21/35 on prion trafficking in real time and space 4. Assess the role of CD21/35 in incunabular prion trafficking

 描述（由申请方提供）：朊病毒疾病或传染性海绵状脑病（TSE）是影响人类、鹿、牛和鸟的致命性神经退行性疾病。PrPC表达产生朊病毒疾病的绝对要求和指导性核酸的缺乏将朊病毒定义为独特的感染因子。朊病毒表现出物种特异性的向性，推断存在独特的朊病毒株，优先感染某些宿主物种，并面临异源宿主物种的传播障碍。然而，传播障碍并不是绝对的。科学界一致认为，绵羊TSE瘙痒病可能突破了牛的传播屏障，导致牛海绵状脑病，随后突破了人类传播屏障，并可能在英国和欧洲造成数百人死于人类TSE克雅氏病的新变体。对人类健康、情感和经济的影响仍然可以在农业、血液和器官捐赠以及潜在的TSE流行病威胁等领域感受到。这一先例提高了其他TSE的真实的可能性，如鹿的慢性消耗性疾病，克服了类似的人类传播障碍。去年的一项突破性发现显示，感染了异源朊病毒菌株的小鼠面临着严重的传播障碍，在脾脏中复制朊病毒比在大脑中更容易。此外，这些脾朊病毒表现出减弱的传输屏障和扩大的主机范围相比，神经源性朊病毒。这些数据质疑了传统的观点，即避免神经组织以避免朊病毒的异种传播，因为更多混杂的朊病毒可能潜伏在神经组织中。来自先前由NIH资助的工作的数据表明，补体受体CD 21/35结合朊病毒和高密度PrPC，并根据所用朊病毒分离物或菌株对朊病毒疾病产生不同的影响。活体动物和整个器官成像的最新进展使我们产生了初步的数据，以支持新的，创新的方法来评估朊病毒的捕获和运输。我们计划测试我们的统一假设，这一建议，CD 21/35控制的过程中的外周朊病毒捕获，运输，菌株选择和异种传播在以下具体目标。1.评估CD 21/35在脾朊病毒株选择和宿主范围扩展中的作用。2.确定CD 21/35和C1 q是否与不同的朊病毒株差异结合3.监测CD 21/35在真实的时空中对朊病毒贩运的影响4.评估CD 21/35在感染性朊病毒贩运中的作用

项目成果

De Novo Generation of a Unique Cervid Prion Strain Using Protein Misfolding Cyclic Amplification.

使用蛋白质错误折叠循环扩增从头生成独特的鹿朊病毒菌株。

• DOI: 10.1128/msphere.00372-16
• 发表时间: 2017
• 期刊: mSphere
• 影响因子: 4.8
• 作者: Meyerett-Reid,Crystal;Wyckoff,AChristy;Spraker,Terry;Pulford,Bruce;Bender,Heather;Zabel,MarkD
• 通讯作者: Zabel,MarkD