Key molecular mechanisms of extraneural pathogenesis and transmission of TSEs

TSE 神经外发病机制和传播的关键分子机制

• 批准号: 8282869
• 负责人: MARK D ZABEL
• 金额: $ 27.97万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8282869
• 关键词: Ablation; Affect; Animal Model; Animals; Backcrossings; Binding; Biochemical; Bovine Spongiform Encephalopathy; Cattle; Chronic; Chronic Wasting Disease; Colorado; Communicable Diseases; Complement; Complement 1q; Complement 3d Receptors; Creutzfeldt-Jakob Syndrome; Data; Deer; Disease; Disease Progression; Disease model; Dose; Early Diagnosis; Early treatment; Endopeptidase K; Engineering; Ensure; Equine mule; Event; Exhibits; Experimental Models; Food Supply; Future; Genetic Techniques; Goals; Human; Immunology; Individual; Infection; Infectious Agent; Ingestion; Investigation; Knockout Mice; Knowledge; Kuru; Left; Ligands; Lymphoid; Lymphoid Tissue; Maps; Methods; Modeling; Molecular; Mus; Nervous system structure; Organ; Pathogenesis; Peripheral; Population; PrP; PrPCWD; PrPSc Proteins; Predisposition; Prevalence; Prion Diseases; Prions; Process; Public Health; Publishing; Research; Resistance; Risk; Role; Safety; Scrapie; Sheep; Site; Testing; Tropism; Work; base; cervid; cobra venom factor; complement system; design; domain mapping; economic impact; mouse model; mutant; novel; offspring; prevent; research study; tool; transmission process

Prion diseases are invariably fatal infectious diseases affecting a wide range of animals. These include chronic wating disease (CWD) of deer and elk, scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt-Jacob disease and kuru in humans. CWD appears to be especially contagious, with suspected horizontal transfer efficiency reaching 90% and estimates of infection among mule deer populations in Colorado reaching 20%. Possible transfer to humans, as exhibited for BSE, has not been systematically disproven and the accompanying risk to public health remains. Moreover, if left unchecked, the ecologic and economic impact could be devastating. Our long-term goals include developing mouse models of CWD to elucidate the molecular mechanisms involved in extraneural prion dissemination, accumulation and replication. We also plan to further our understanding of these processes using novel as well as established mouse models of scrapie, with the ultimate goal of developing further CWD models in mice based on these data. Our specific hypothesis states that certain components of the Complement system enable optimal prion capture, replication and neuroinvasion in CWD and scrapie. We derive this hypothesis from 1) previously published data demonstrating that partial or complete depletion of Complement components C1q, C3 and CD21 delays splenic prion accumulation and replication; and impedes or even prevents disease in murine models of scrapie; and 2) previously published data showing significant PrPCWD localization in CD21-expressing lymphoid tissue from deer and 3) our current data that shows murine CD21/35 interacts with PrPSc without its endogenous ligands C3 and C4. We plan to extend this work and initiate new investigations with the following specific aims: 1) Test Complement-deficient Tg(CerPrP) mouse models. 2) Test the horizontal transmissibility of CWD in Tg(cerPrP) mice. 3) Extend our investigation into the role of Complement in peripheral prion pathogenesis using murine scrapie models. Our data strongly suggest that PrPSC can interact with sites on CD21/35 distinct from those that bind C3 cleavage products. We will map these sites by creating CD21/35 truncation mutants and analyzing their ability to bind PrPSc and PrPCWD. PROJECT NARRATIVE Interspecies transmission from BSE-infected cattle in the UK to humans has almost certainly occurred, and has not been disproved for other TSEs, including scrapie and CWD. Determining mechanisms of transmission of scrapie and CWD, which exhibit incredibly efficient Intraspecies transmission, is vital to ensuring the safety of the nation's food supply and, therefore, public health.

朊病毒疾病总是致命的传染病，影响范围广泛， 动物这些疾病包括鹿和麋鹿的慢性萎缩性疾病（CWD）， 绵羊、牛海绵状脑病（BSE）和克罗伊茨费尔特-雅各布 疾病和库鲁病。慢性消耗病似乎特别具有传染性， 疑似水平转移效率达到90%， 在科罗拉多的黑尾鹿种群中达到了20%。可能转移到 人类，如BSE所显示的，尚未被系统地证明是错误的， 对公众健康的伴随风险依然存在。此外，如果不加以检查， 生态和经济影响可能是毁灭性的。我们的长期目标包括 开发慢性消耗病小鼠模型以阐明相关的分子机制 朊病毒在神经内的传播、积累和复制。我们还计划 进一步了解这些过程，使用新的以及建立 羊瘙痒症小鼠模型，最终目标是开发更多的CWD模型， 老鼠根据这些数据。我们的特定假设表明， 补体系统能够实现最佳朊病毒捕获、复制和神经侵入 慢性消耗病和羊瘙痒病我们从1）以前发表的数据得出这一假设 证明补体成分C1 q的部分或完全消耗， C3和CD 21延迟脾朊病毒积累和复制;并阻碍或 甚至可以预防瘙痒症小鼠模型中的疾病; 2）先前发表的数据 显示PrPCWD在CD 21表达淋巴组织中的显著定位， 鹿和3）我们目前的数据显示，鼠CD 21/35与PrPSc相互作用， 其内源性配体C3和C4。我们计划扩大这项工作，并启动新的 具有以下特定目的的研究：1）测试补体缺乏 Tg（CerPrP）小鼠模型。2)CWD的水平传递率测试 Tg（cerPrP）小鼠。3)将我们的研究扩展到补体在 使用鼠瘙痒病模型的外周朊病毒发病机制。我们的数据显示 提示PrPSC可以与CD 21/35上不同于结合那些位点相互作用 C3裂解产物。我们将通过创建CD 21/35截断来映射这些位点 突变体并分析它们结合PrPSc和PrPCWD的能力。项目叙述 从英国感染疯牛病的牛到人类的种间传播几乎肯定会发生， 对于其他TSE，包括羊瘙痒症和慢性消耗病，没有被证明是错误的。决定机制 羊瘙痒病和慢性消耗病的传播，表现出令人难以置信的有效种内传播，是至关重要的， 确保国家食品供应的安全，从而确保公众健康。

项目成果

Complement Regulatory Protein Factor H Is a Soluble Prion Receptor That Potentiates Peripheral Prion Pathogenesis.

补体调节蛋白因子 H 是一种可溶性朊病毒受体，可增强外周朊病毒发病机制。

• DOI: 10.4049/jimmunol.1701100
• 发表时间: 2017
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Kane,SarahJ;Farley,TaylorK;Gordon,ElizabethO;Estep,Joshua;Bender,HeatherR;Moreno,JulieA;Bartz,Jason;Telling,GlennC;Pickering,MatthewC;Zabel,MarkD
• 通讯作者: Zabel,MarkD

Genetic depletion of complement receptors CD21/35 prevents terminal prion disease in a mouse model of chronic wasting disease.

• DOI: 10.4049/jimmunol.1201579
• 发表时间: 2012-11-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Michel B;Ferguson A;Johnson T;Bender H;Meyerett-Reid C;Pulford B;von Teichman A;Seelig D;Weis JH;Telling GC;Aguzzi A;Zabel MD
• 通讯作者: Zabel MD

Incunabular immunological events in prion trafficking.

朊病毒贩运中的不期免疫事件。

• DOI: 10.1038/srep00440
• 发表时间: 2012
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Michel,Brady;Meyerett-Reid,Crystal;Johnson,Theodore;Ferguson,Adam;Wyckoff,Christy;Pulford,Bruce;Bender,Heather;Avery,Anne;Telling,Glenn;Dow,Steven;Zabel,MarkD
• 通讯作者: Zabel,MarkD

Relative Impact of Complement Receptors CD21/35 (Cr2/1) on Scrapie Pathogenesis in Mice.

• DOI: 10.1128/mspheredirect.00493-17
• 发表时间: 2017-11
• 期刊: mSphere
• 影响因子: 4.8
• 作者: Kane SJ;Swanson E;Gordon EO;Rocha S;Bender HR;Donius LR;Aguzzi A;Hannan JP;Zabel MD
• 通讯作者: Zabel MD

Monitoring immune cells trafficking fluorescent prion rods hours after intraperitoneal infection.

腹膜内感染数小时后监测免疫细胞运输荧光朊病毒棒。

• DOI: 10.3791/2349
• 发表时间: 2010
• 期刊: Journal of visualized experiments : JoVE
• 作者: Johnson,TheodoreE;Michel,BradyA;Meyerett,Crystal;Duffy,Angela;Avery,Anne;Dow,Steven;Zabel,MarkD
• 通讯作者: Zabel,MarkD