Impact of Microparticles on Oral TSE Infections

描述(申请人提供)：Prion疾病不可避免地是致命的、可传播的疾病，在长时间潜伏期后会导致进行性神经功能障碍。口腔传播是疯牛病、瘙痒病和TME的主要感染途径，也是vCJD和CWD的疑似传播途径。TSE有几个共同的特征，包括积累一种疾病特有的结构异常形式的PrPSc。我们最近证明了普鲁恩与土壤、粘土矿物和二氧化硅结合(Johnson等人，2007年)。我们分析了PrPSc与蒙脱石粘土(MTE)的结合，发现它非常亲和。当实验动物口服PrPSc与MTE结合时，与只使用PrPSc观察到的相比，更多的动物在较短的潜伏期内死于疾病。口服传播实验的生存分析表明，与粘土结合的普恩病毒的口服传播性大约是非结合剂的700倍(Johnson等人，2007年)。整个土壤都有类似的效果；三个测试土壤中有两个增强了传播，第三个的传染性不低于未结合的PrPSc(Johnson等人，2007年)。我们的研究支持这样的假设，即土壤和土壤微粒与PrPSc结合，增强了瘙痒病和CWD的疾病传播。在这项应用中，我们建议检查土壤微粒对CWD在鹿(SA1)中传播的影响。这些研究将强调整个土壤，它们结合CWD病原体的能力，以及这种相互作用对CWD疾病传播的影响。在SA2中，我们将通过检测粘粒结合蛋白的耐降解性、粘粒结合剂的摄取以及粘粒结合蛋白的聚集状态等生物物理参数来确定粘粒结合蛋白增加口腔可传递性的机制(S)。除土壤外，许多其他物质中也含有微粒。肉骨粉(MBM)是一种常用的牛食品补充剂，被认为是欧洲疯牛病的罪魁祸首。我们提供的数据表明MBM含有丰富的微粒，并将测试MBM关联剂是否类似于MTE增强口服传播性。最后，我们将确定在肠道中形成的内源性钙(Ca)磷酸微粒是否会促进TSE感染。这些研究将评估TSE试剂吸附到钙磷酸盐上的传染性，并检查钙含量减少的动物的口腔传染性。我们假设，钙磷微粒减少的动物将不太容易感染TSE，并且毒剂对肠道磷酸钙的吸附是启动口腔TSE感染的途径中的一步。与公共卫生相关：Prion病是一种可传播的神经疾病，可影响动物(绵羊瘙痒病、鹿慢性衰弱病、牛海绵状脑病)和人类(CreutzFeldt-Jakob病和Kuru)。环境保持和成为绵羊瘙痒病和鹿瘟的感染源的潜力是有充分证据的，毫无疑问，涉及低水平的感染剂的口头传播。由于通常情况下，口腔传播不是感染易感动物的有效手段，我们假设土壤在增强口腔传播中起到了作用。我们的研究支持这样的假设，即土壤和土壤微粒与PrPSc结合，增强了瘙痒病和CWD的疾病传播。

DESCRIPTION (provided by applicant): Prion diseases are inevitably fatal, transmissible disorders inducing a progressive neurologic dysfunction after a prolonged incubation period. Oral transmission is the primary route of infection for BSE, scrapie and TME and is the suspected route of transmission for vCJD and CWD. TSEs share several hallmark characteristics including the accumulation of a disease-specific structurally abnormal form of the prion protein (PrPSc). We have recently demonstrated that prions bind to soil, clay minerals and silicon dioxide (Johnson et al., 2007). We have analyzed the binding of PrPSc to montmorillonite clay (Mte) and found it to be extremely avid. When laboratory animals are orally challenged with PrPSc bound to Mte, more animals succumbed to disease with shorter incubation periods than were observed with just PrPSc. Survival analysis of oral transmission experiments demonstrate that prions bound to clay are approximately 700 times more orally transmissible than unbound agent (Johnson et al., 2007). Whole soils have a similar effect; two of three tested soils enhance transmission and the third is no less infectious than unbound PrPSc (Johnson et al., 2007). Our studies support the hypothesis that soil and soil microparticles bind to prion protein (PrPSc) enhancing disease transmission for scrapie and CWD. In this application, we propose to examine the effect of soil microparticles on CWD transmission in deer (SA1). These studies will emphasize whole soils, their ability to bind CWD agent and the impact of this interaction on CWD disease transmission. In SA2, we will determine the mechanism(s) by which clay-bound prions have increased orally transmissible by examining the resistance to degradation, uptake of clay-bound agent and the aggregation state and other biophysical parameters of PrPSc bound to clay. Microparticles are found in many other substances than soil. Meat and bone meal (MBM), a commonly used cattle food supplement thought responsible for BSE in Europe. We present data demonstrating MBM is rich in microparticles and will test if MBM-associated agent enhances oral transmissibility similar to Mte. Finally we will determine if endogenous calcium (Ca) phosphate microparticles, formed in the intestine, promote TSE infection. These studies will assess the infectivity of TSE agent sorbed to Ca phosphate and examining oral infectivity in animals with reduced Ca content. We hypothesize that animals with reduced Ca phosphate microparticles will be less susceptible to TSE infection and that agent sorption to intestinal calcium phosphate represents a step in the pathway by which oral TSE infections in initiated. PUBLIC HEALTH RELEVANCE: Prion diseases are transmissible neurologic disorders that can affect animals (sheep scrapie, cervid chronic wasting disease, bovine spongiform encephalopathy) and humans (Creutzfeldt-Jakob disease and Kuru). The potential for the environment to maintain and become a source of infectivity for sheep scrapie and cervid CWD is well documented and, undoubtedly, involves oral transmission of low levels of infectious agent. Since oral transmission is, in general, not an efficient means of infecting susceptible animals, we hypothesize a role for soil in the enhancement of oral transmission. Our studies support the hypothesis that soil and soil microparticles bind to prion protein (PrPSc) enhancing disease transmission for scrapie and CWD.