Impact of Microparticles on Oral TSE Infections

微粒对口腔 TSE 感染的影响

• 批准号: 7597236
• 负责人: JUDD M. AIKEN
• 金额: $ 43.21万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 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/7597236
• 关键词: Affect; Animals; Binding; Biological; Bovine Spongiform Encephalopathy; Calcium; Cattle; Characteristics; Chronic Wasting Disease; Clinical; Complex; Confidence Intervals; Cox Proportional Hazards Models; Creutzfeldt-Jakob Syndrome; Data; Deer; Disease; Dose; Encephalopathies; 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; PrPSc Proteins; Prion Diseases; Prions; Proteins; Resistance; Rodent Model; Role; Route; Ruminants; Scrapie; Sheep; Silicon Dioxide; Sodium Chloride; Soil; Source; Survival Analysis; Testing; Texture; Time; Transgenic Mice; Variant; aluminosilicate; bone meal; calcium phosphate; cervid; clay; disease transmission; feeding; gastrointestinal system; nervous system disorder; particle; public health relevance; research study; transmission process; uptake

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）：病毒疾病不可避免地致命，可传染性疾病，在长时间的孵育期间诱导了进行性神经系统功能障碍。口头传播是BSE，CRAPIE和TME感染的主要途径，是VCJD和CWD的可疑传播途径。 TSE具有多种标志性的特征，包括疾病特异性在结构异常形式的prion蛋白（PRPSC）的积累。我们最近证明，王子与土壤，粘土矿物质和二氧化硅结合（Johnson等，2007）。我们已经分析了PRPSC与Montmorillonite粘土（MTE）的结合，并发现它非常狂热。当实验室动物被与MTE结合的PRPSC口头挑战时，与仅在PRPSC中观察到的相比，随着孵化时间较短的疾病屈服于疾病。口服传播实验的生存分析表明，与未结合药物相比，与粘土结合的王子的口服传播约为700倍（Johnson等，2007）。整个土壤具有相似的作用；三个测试的土壤中有两个增强了传播，而第三个则具有感染力，而不是未结合的PRPSC（Johnson等，2007）。我们的研究支持了以下假设：土壤和土壤微粒与prion蛋白（PRPSC）增强疾病传播的疾病和CWD的假设。在此应用中，我们建议检查土壤微粒对鹿中CWD传播的影响（SA1）。这些研究将强调整个土壤，结合CWD剂的能力以及这种相互作用对CWD疾病传播的影响。在SA2中，我们将确定通过检查降解性，粘土结合剂的耐药性以及PRPSC的聚集状态以及PRPSC的其他生物物理参数的耐药性来确定粘土结合的prions提高口服的机制。除土壤以外的许多其他物质中发现了微粒。肉类和骨粉（MBM），一种常用的牛食品补充剂，认为负责欧洲的BSE。我们提供了证明MBM富含微粒的数据，并将测试MBM相关剂是否增强了类似于MTE的口服传递性。最后，我们将确定内源性钙（Ca）磷酸盐微粒是否在肠中形成，促进TSE感染。这些研究将评估吸附到CA磷酸盐的TSE药物的感染性，并检查Ca含量降低的动物的口服感染性。我们假设磷酸盐微粒降低的动物不太容易受到TSE感染的影响，并且对磷酸盐肠道钙的吸附代表了途径中口服TSE感染的途径迈出的一步。公共卫生相关性：prion疾病是可传播的神经系统疾病，会影响动物（绵羊crap，子宫颈慢性浪费疾病，牛海绵状脑病）和人类（Creutzfeldt-Jakob病和kuru）。环境维持和成为绵羊crap和子宫颈CWD的感染性的潜力已得到充分记载，无疑涉及低水平的感染剂的口服传播。通常，由于口服传播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服传播中的作用。我们的研究支持了以下假设：土壤和土壤微粒与prion蛋白（PRPSC）增强疾病传播的疾病和CWD的假设。