Key molecular mechanisms of extraneural pathogenesis and transmission of TSEs

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）和克雅氏病 疾病和库鲁病。CWD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 发展慢性消耗病的小鼠模型，以阐明所涉及的分子机制 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 慢性消耗病和瘙痒症。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。

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.