Key molecular mechanisms of extraneural pathogenesis and transmission of TSEs

描述(申请人提供)：Pron病总是致命的传染病，影响广泛的动物。这些疾病包括鹿和麋鹿的慢性消耗性疾病(CWD)，绵羊的瘙痒病，牛的牛海绵状脑病(BSE)，以及人类的克雅氏病和库鲁病。CWD似乎具有特别的传染性，疑似水平传播效率达到90%，科罗拉多州骡鹿种群的感染估计达到20%。就像疯牛病所展示的那样，向人类传播的可能性尚未被系统地证明是错误的，随之而来的对公共卫生的风险仍然存在。此外，如果不加以控制，其生态和经济影响可能是毁灭性的。我们的长期目标包括建立慢性萎缩性脑病的小鼠模型，以阐明神经外病毒传播、积累和复制所涉及的分子机制。我们还计划使用新的和已建立的瘙痒病小鼠模型来加深我们对这些过程的理解，最终目标是在这些数据的基础上开发进一步的CWD小鼠模型。我们的特定假设表明，补体系统的某些组件能够在CWD和瘙痒病中实现最佳的Prion捕获、复制和神经侵袭。我们根据以下假设得出这一假说：1)先前发表的数据表明部分或全部耗尽补体成分C1q、C3和CD21会延迟脾病毒的PrPSc的积累和复制，并阻止甚至预防小鼠瘙痒病模型中的疾病；2)先前发表的数据显示PrPCWD在鹿的CD21表达的淋巴组织中有显著的定位；3)我们目前的数据表明小鼠CD21/35在没有其内源性配体C3和C4的情况下与PrPSc相互作用。我们计划扩展这项工作并启动新的研究，具体目标如下：1)检测补体缺陷TG(CerPrP)小鼠模型。2)测定CWD在Tg(CerPrP)小鼠体内的水平传播率。3)利用小鼠瘙痒病模型进一步研究补体在外周病毒致病机制中的作用。我们的数据有力地表明PrPSC可以与CD21/35上的位点相互作用，不同于那些结合C3切割产物的位点。我们将通过创建CD21/35截断突变体并分析它们与PrPSc和PrPCWD结合的能力来定位这些位点。公共卫生相关性：在英国，感染疯牛病的牛几乎肯定已经发生了从感染疯牛病到人类的物种间传播，并没有在其他疯牛病中被证明是错误的，包括瘙痒病和慢性萎缩性脑病。确定瘙痒病和慢性萎缩性胃病的传播机制对于确保国家食品供应安全和公共卫生至关重要，因为它们显示出令人难以置信的种内传播。

DESCRIPTION (provided by applicant): Prion diseases are invariably fatal infectious diseases affecting a wide range of animals. These include chronic wasting 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. PUBLIC HEALTH RELEVANCE: 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.