The influence of the GALT in TSE agent neuroinvasion from the large intestine

传染性海绵状脑病 (TSE) 是一种长期疾病，会对大脑神经造成广泛损害。如果没有治愈方法，TSE 疾病总是致命的。这些疾病影响动物和人类，包括人类的克雅氏病 (CJD)、牛的牛海绵状脑病、黑尾鹿和麋鹿的慢性消耗性疾病以及绵羊和山羊的痒病。一些动物物种和人类在食用受 TSE 物质污染的食物后，或通过移植受 TSE 物质污染的组织或组织产品（例如：输入来自受变异克雅氏病感染的供体的血液）后，感染了这些疾病。关于传染性 TSE 病原体从暴露部位（例如肠道）到大脑的路径仍然存在许多问题，并在大脑中对神经细胞造成损害。我们已经证明，接触 TSE 药物后不久，它们首先会在淋巴组织（小肠中的派尔氏淋巴结、淋巴结和脾脏）内聚集并聚集，然后再扩散到大脑。许多 TSE 物质必须在这些淋巴组织中积聚，然后才能扩散到大脑（这一过程称为神经侵袭），最终导致神经变性和死亡。口服暴露后，TSE 制剂还会在大肠（如阑尾）的淋巴组织内积聚。然而，大肠对口腔 TSE 发病机制的贡献尚不清楚，并且大多被忽视。这是不幸的，因为大肠可能是影响疾病易感性的 TSE 物质积累的重要早期部位。例如，大肠内的炎症或病理可能影响疾病易感性。在当前的项目中，将创建只在大肠中含有淋巴组织的小鼠。这些小鼠将用于测试以下假设：大肠中的淋巴组织是 TSE 物质积累的重要部位，影响疾病的发病机制和易感性。为了实现这一目标，将解决以下可测量的目标： 目标 1 - 表征小肠和大肠内淋巴组织的发育和状态 目标 2 - 确定淋巴组织对大肠 TSE 病原体神经侵袭的影响 最后，其他肠道病原体可能对 TSE 易感性的影响尚不清楚。例如，这些病原体在肠道中引起的病理可能会增加 TSE 制剂的摄取，而炎症细胞的流入可能会破坏 TSE 制剂，从而降低敏感性。在目标 3 中，将确定常见肠道寄生虫感染对口腔 TSE 发病机制的影响。这些数据将预测胃肠道病原体感染如何影响 TSE 易感性。目标3-确定胃肠道病原体感染对口腔TSE发病机制的影响目前，缺乏治疗TSE疾病的有效治疗剂和预防剂。此外，没有可靠的临床前诊断测试可用。彻底了解 TSE 发病机制的早期事件将有助于确定风险、开发临床前诊断和治疗方法，特别是开发 TSE 特异性粘膜疫苗。

Transmissible spongiform encephalophathies (TSEs) are prolonged diseases which cause extensive damage to nerves in the brain. In the absence of a cure TSE diseases are invariably fatal. These diseases affect both animals and humans, and include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy in cattle, chronic wasting disease in mule deer and elk, and scrapie in sheep and goats. Some animal species and humans have become infected with these diseases after eating TSE agent-contaminated food, or through transplantation of TSE agent-contaminated tissues or tissue products (eg: transfusion of blood from a variant CJD-infected donor). Many questions remain concerning the route the infectious TSE agent takes from the site of exposure (eg: intestine) to the brain where it causes damage to nerve cells. We have shown that soon after exposure TSE agents first target and accumulate within lymphoid tissues (Peyer's patches in the small intestine, lymph nodes and spleen) before they spread to the brain. Many TSE agents must accumulate in these lymphoid tissues before they can subsequently spread to the brain (a process termed neuroinvasion) where they ultimately cause neurodegeneration and death. After oral exposure TSE agents also accumulate within lymphoid tissues in the large intestine such as the appendix. However, the contribution of the large intestine to oral TSE pathogenesis is unknown and has been mostly overlooked. This is unfortunate as the large intestine may be an important early site of TSE agent accumulation that influences disease susceptibility. For example, inflammation or pathology within the large intestine may affect disease susceptibility. In the current project, mice will be created that contain lymphoid tissues in the large intestine only. These mice will be used to test the hypothesis that lymphoid tissues in the large intestine are important sites of TSE agent accumulation which influence disease pathogenesis and susceptibility. To achieve this, the following measurable objectives will be addressed: Objective 1- Characterise the development and status of the lymphoid tissues within the small and large intestines Objective 2- Determine the influence of lymphoid tissues in TSE agent neuroinvasion from the large intestine Finally, the effects that other intestinal pathogens may have on TSE susceptibility are not known. For example, the pathology that these pathogens cause in the intestine may increase the uptake of the TSE agent, whereas an influx of inflammatory cells may destroy the TSE agent reducing susceptibility. In Objective 3 the effects of infection with a common gut parasite on oral TSE pathogenesis will be determined. These data will provide predictions on how infection with gastrointestinal pathogens may influence TSE susceptibility. Objective 3- Determine the influence of infection with a gastrointestinal pathogen on oral TSE pathogenesis Currently, effective therapeutics and prophylactics to treat TSE diseases are lacking. Furthermore, no reliable preclinical diagnostic test is available. A thorough understanding of the early events in TSE pathogenesis will aid the determination of risk, the development of pre-clinical diagnostics and therapeutics, especially the development TSE-specific mucosal vaccines.