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

传染性海绵状脑病（TSE）是一种长期的疾病，会对大脑神经造成广泛的损害。在没有治愈方法的情况下，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病以及绵羊和山羊的瘙痒症。一些动物物种和人类在食用TSE病原体污染的食物后感染了这些疾病，或者通过移植TSE病原体污染的组织或组织产品（例如：从变异CJD感染的供体输血）。关于传染性TSE因子从暴露部位（例如：肠）到大脑的途径，仍存在许多问题，在大脑中它会对神经细胞造成损伤。我们已经证明，在暴露后不久，TSE制剂首先靶向淋巴组织（小肠、淋巴结和脾脏中的派尔集合淋巴结）并在淋巴组织中蓄积，然后扩散到大脑。许多TSE因子必须在这些淋巴组织中积累，然后才能扩散到大脑（称为神经侵入的过程），最终导致神经变性和死亡。经口暴露后，TSE因子也在大肠淋巴组织（如阑尾）内蓄积。然而，大肠对口腔TSE发病机制的贡献是未知的，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因子积聚的重要早期部位。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，将创建仅在大肠中含有淋巴组织的小鼠。这些小鼠将用于检验以下假设：大肠中的淋巴组织是影响疾病发病机制和易感性的TSE因子蓄积的重要部位。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TSE因子从大肠神经侵入的影响最后，其他肠道病原体可能对TSE易感性的影响尚不清楚。例如，这些病原体在肠中引起的病理可能增加TSE试剂的摄取，而炎性细胞的流入可能破坏TSE试剂，降低易感性。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。这些数据将提供关于胃肠道病原体感染如何影响TSE易感性的预测。目的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疾病的有效疗法和药物。此外，没有可靠的临床前诊断测试可用。全面了解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.