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的、可传播的疾病，经过长时间的潜伏期，可引起进行性神经功能障碍。口腔传播是疯牛病、痒病和TME的主要感染途径，也是vCJD和CWD的疑似传播途径。tse具有几个标志性特征，包括积累疾病特异性结构异常形式的朊病毒蛋白（PrPSc）。我们最近证明，朊病毒与土壤、粘土矿物和二氧化硅结合（Johnson et al., 2007）。我们分析了PrPSc与蒙脱土（Mte）的结合，发现它的结合非常强烈。当实验动物口服与Mte结合的PrPSc时，与仅使用PrPSc相比，更多的动物在较短的潜伏期内死于疾病。口腔传播实验的生存分析表明，与粘土结合的朊病毒的口腔传播能力约为未结合剂的700倍（Johnson et al., 2007）。整个土壤也有类似的效果；三种测试土壤中的两种增强了传播，第三种土壤的传染性并不低于未结合的PrPSc （Johnson等人，2007年）。我们的研究支持了土壤和土壤微粒与朊病毒蛋白（PrPSc）结合增强瘙痒病和CWD疾病传播的假设。在这个应用中，我们建议研究土壤微粒对鹿CWD传播的影响（SA1）。这些研究将强调整个土壤，它们结合CWD药剂的能力以及这种相互作用对CWD疾病传播的影响。在SA2中，我们将通过检测与粘土结合的PrPSc对降解的抵抗力、对粘土结合剂的吸收以及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。除土壤外，微粒还存在于许多其他物质中。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。我们提供的数据表明MBM含有丰富的微粒，并将测试MBM相关剂是否会像Mte一样增强口腔传播。最后，我们将确定肠道内形成的内源性钙（Ca）磷酸微颗粒是否会促进TSE感染。这些研究将评估TSE剂吸附在磷酸钙上的感染性，并检查钙含量降低的动物的口腔感染性。我们假设，磷酸钙微颗粒减少的动物对TSE感染的易感性较低，并且药物对肠道磷酸钙的吸收代表了口腔TSE感染开始的途径中的一个步骤。公共卫生相关性：朊病毒疾病是可影响动物（羊痒病、宫颈慢性消耗性疾病、牛海绵状脑病）和人类（克雅氏病和库鲁病）的传染性神经系统疾病。环境保持并成为羊痒病和宫颈CWD传染源的可能性已被充分记录，并且无疑涉及低水平传染因子的口腔传播。由于口腔传播通常不是感染易感动物的有效手段，因此我们假设土壤在增强口腔传播方面发挥了作用。我们的研究支持了土壤和土壤微粒与朊病毒蛋白（PrPSc）结合增强瘙痒病和CWD疾病传播的假设。

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.