Impact of Microparticles on Oral TSE Infections

描述（由申请人提供）：朊病毒疾病是一种不可避免的致命性传染性疾病，在延长的潜伏期后会引起进行性神经功能障碍。经口传播是BSE、瘙痒症和TME的主要感染途径，也是vCJD和CWD的疑似传播途径。TSE共有几个标志性特征，包括疾病特异性结构异常形式的朊病毒蛋白（PrPSc）的积累。我们最近已经证明朊病毒与土壤、粘土矿物和二氧化硅结合（约翰逊等人，2007年）。我们分析了PrPSc与蒙脱石粘土（Mte）的结合，发现它是非常活泼的。当实验室动物口服与Mte结合的PrPSc时，更多的动物死于疾病，潜伏期比仅用PrPSc观察到的更短。经口传播实验的存活分析表明，与粘土结合的朊病毒经口传播的能力比未结合的朊病毒高约700倍（约翰逊等人，2007年）。整个土壤具有类似的效果;三种测试土壤中的两种增强了传播，第三种的感染性不低于未结合的PrPSc（约翰逊等人，2007年）。我们的研究支持这一假设，土壤和土壤微粒结合朊病毒蛋白（PrPSc）增强疾病传播的瘙痒症和慢性消耗病。在这个应用中，我们建议检查的影响，土壤微粒对慢性消耗病传播鹿（SA 1）。这些研究将强调整个土壤，它们结合CWD试剂的能力以及这种相互作用对CWD疾病传播的影响。在SA 2中，我们将通过检查对降解的抗性、粘土结合剂的摄取和PrPSc与粘土结合的聚集状态和其他生物物理参数来确定粘土结合朊病毒增加口腔传播的机制。微粒存在于土壤以外的许多其他物质中。肉骨粉（MBM），一种常用的牛饲料补充剂，被认为是欧洲疯牛病的罪魁祸首。我们目前的数据表明，MBM是富含微粒，并将测试MBM相关的代理商，提高类似于Mte的口腔传播。最后，我们将确定在肠道中形成的内源性磷酸钙（Ca）微粒是否促进TSE感染。这些研究将评估吸附到磷酸钙上的TSE病原体的感染性，并检查钙含量降低的动物的经口感染性。我们假设磷酸钙微粒减少的动物对TSE感染的敏感性较低，并且药物对肠道磷酸钙的吸附代表了口服TSE感染启动途径中的一个步骤。公共卫生相关性：朊病毒病是一种传染性神经系统疾病，可影响动物（羊瘙痒症、鹿慢性消耗病、牛海绵状脑病）和人类（克雅氏病和库鲁病）。环境维持并成为绵羊瘙痒病和鹿慢性消耗病传染源的可能性已得到充分证明，无疑涉及低水平传染因子的口服传播。由于口腔传播，在一般情况下，不是一个有效的手段感染易感动物，我们假设的作用，土壤在增强口腔传播。我们的研究支持这一假设，土壤和土壤微粒结合朊病毒蛋白（PrPSc）增强疾病传播的瘙痒症和慢性消耗病。

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.