Key molecular mechanisms of extraneural pathogenesis and transmission of TSEs

描述（由申请人提供）：朊病毒疾病总是致命的传染病，影响范围广泛的动物。这些疾病包括鹿和麋鹿的慢性消耗病、绵羊的痒病、牛的牛海绵状脑病以及人类的克雅氏病和库鲁病。慢性消耗病似乎特别具有传染性，怀疑水平转移效率达到90%，估计科罗拉多的黑尾鹿种群之间的感染率达到20%。BSE所显示的可能转移到人类的可能性尚未被系统地证明是错误的，对公共卫生的伴随风险仍然存在。此外，如果不加以控制，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消耗病的小鼠模型，以阐明朊病毒在神经内传播、积累和复制的分子机制。我们还计划使用新的以及已建立的瘙痒症小鼠模型来进一步理解这些过程，最终目标是基于这些数据在小鼠中开发进一步的CWD模型。我们的特定假设指出，补体系统的某些组成部分，使最佳的朊病毒捕获，复制和神经侵袭慢性消耗病和瘙痒症。我们从1）先前发表的数据中得出这一假设，这些数据表明补体成分C1 q、C3和CD 21的部分或完全消耗延迟了脾朊病毒的积累和复制;并且在瘙痒症的小鼠模型中阻碍或甚至预防疾病;和2）先前发表的数据显示在鹿的表达CD 21的淋巴组织中有显著的PrPCWD定位，和3）我们目前的数据显示鼠的CD 21/CD 22/CD 21/CD 35与PrPSc相互作用，而没有其内源性配体C3和C4。我们计划扩展这项工作，并启动新的研究，具体目标如下：1）测试补体缺陷型Tg（CerPrP）小鼠模型。2)测试CWD在Tg（cerPrP）小鼠中的水平传递性。3)扩展我们的研究补体在外周朊病毒发病机制中的作用，使用小鼠瘙痒症模型。我们的数据有力地表明，PrPSC可以与CD 21/35上的位点相互作用，这些位点与结合C3裂解产物的位点不同。我们将通过创建CD 21/35截短突变体并分析其结合PrPSc和PrPCWD的能力来绘制这些位点。 公共卫生相关性：几乎可以肯定，英国疯牛病感染牛向人类的种间传播已经发生，并且尚未证明其他TSE，包括瘙痒症和慢性消耗病。确定羊瘙痒病和慢性消耗病的传播机制，表现出令人难以置信的有效种内传播，对于确保国家食品供应的安全至关重要，因此，公共卫生。

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.