Impact of Microparticles on Oral TSE Infections

微粒对口腔 TSE 感染的影响

基本信息

批准号：
7469666
负责人：
JUDD M. AIKEN
金额：
$ 54.08万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7469666
关键词：
Affect Animals Binding Biological Bovine Spongiform Encephalopathy Calcium Cattle Characteristics Chronic Chronic Wasting Disease Clinical Complex Confidence Intervals Cox Proportional Hazards Models Creutzfeldt-Jakob Syndrome Data Deer Disease Dose Encephalopathies Endopeptidases Environment Europe Food Supplements Gastrointestinal tract structure Human Infection Infectious Agent Intestines Knowledge Kuru Laboratory Animals Meat Minerals Mink Montmorillonite Mouth Diseases Neuraxis Neurologic Dysfunctions Oral Particle Size Pathway interactions Penetrance Peptide Hydrolases Personal Satisfaction PrPSc Proteins Prion Diseases Prions Proteins Public Health Resistance Rodent Model Role Route Ruminants Scrapie Sheep Silicon Dioxide Sodium Chloride Soil Source Survival Analysis Testing Texture Thinking Time Transgenic Mice Variant Wasting Syndrome aluminosilicate bone meal calcium phosphate cervid clay disease transmission feeding gastrointestinal system nervous system disorder particle research study transmission process uptake

项目摘要

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.

描述（由申请人提供）：朊病毒病是不可避免的致命性传染性疾病，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 BSE、痒病和 TME 的主要感染途径，也是 vCJD 和 CWD 的可疑传播途径。 TSE 有几个共同的标志特征，包括疾病特异性结构异常形式的朊病毒蛋白 (PrPSc) 的积累。我们最近证明朊病毒与土壤、粘土矿物和二氧化硅结合（Johnson 等，2007）。我们分析了 PrPSc 与蒙脱石粘土 (Mte) 的结合，发现它的结合力非常强。当实验动物口服与 Mte 结合的 PrPSc 时，与仅使用 PrPSc 相比，更多的动物在更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比未结合的朊病毒高约 700 倍（Johnson 等人，2007 年）。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，第三种的传染性不低于未结合的 PrPSc（Johnson 等，2007）。我们的研究支持这样的假设：土壤和土壤微粒与朊病毒蛋白 (PrPSc) 结合，增强瘙痒病和 CWD 疾病的传播。在此应用中，我们建议检查土壤微粒对鹿 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，我们将通过检查粘土结合剂的降解抗性、粘土结合剂的摄取以及与粘土结合的 PrPSc 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。除土壤外，许多其他物质中也发现了微粒。肉骨粉（MBM），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 富含微粒，并将测试 MBM 相关药物是否能像 Mte 一样增强口腔传播性。最后，我们将确定肠道中形成的内源性磷酸钙 (Ca) 微粒是否会促进 TSE 感染。这些研究将评估磷酸钙吸附的 TSE 剂的感染性，并检查钙含量降低的动物的口腔感染性。我们假设磷酸钙微粒减少的动物将不太容易受到 TSE 感染，并且肠道磷酸钙的吸附剂代表了口腔 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）。环境有可能维持并成为绵羊痒病和宫颈慢性病的传染源，这一点已有充分记录，并且毫无疑问涉及低水平传染源的口腔传播。由于口腔传播通常不是感染易感动物的有效方式，因此我们假设土壤在增强口腔传播方面发挥着作用。我们的研究支持这样的假设：土壤和土壤微粒与朊病毒蛋白 (PrPSc) 结合，增强瘙痒症和 CWD 疾病的传播。