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，会对大脑中的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。这些疾病对动物和人类都有影响，包括人类的克雅氏病(CJD)，牛的牛海绵状脑病，骡鹿和麋鹿的慢性消耗性疾病，以及绵羊和山羊的瘙痒病。一些动物物种和人类在食用受TSE制剂污染的食物后，或通过移植受TSE制剂污染的组织或组织产品(例如，从感染CJD的变种捐赠者输血)，感染了这些疾病。关于传染性TSE病原体从接触部位(如肠道)进入大脑并对神经细胞造成损害的途径，仍有许多问题。我们已经证明，暴露后不久，TSE制剂首先靶向并在淋巴组织(小肠、淋巴结和脾中的Peyer‘s斑块)内积聚，然后再扩散到大脑。许多TSE药物必须在这些淋巴组织中积聚，然后才能随后扩散到大脑(这一过程称为神经侵袭)，最终导致神经退化和死亡。口服染毒后，TSE制剂也会在大肠的淋巴组织内积聚，如阑尾。然而，大肠在口腔TSE发病机制中的作用尚不清楚，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病原体积累的重要早期部位。例如，大肠内的炎症或病理可能会影响疾病的易感性。在目前的项目中，将创造出仅在大肠中包含淋巴组织的小鼠。这些小鼠将被用来检验这样的假设，即大肠中的淋巴组织是影响疾病发病机制和易感性的TSE病原体聚集的重要部位。为了实现这一目标，将解决以下可测量的目标：目的1-表征小肠和大肠内淋巴组织的发育和状况目的2-确定淋巴组织在TSE制剂从大肠神经侵袭中的影响最后，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介质的摄取，而炎症细胞的涌入可能会破坏TSE介质，降低易感性。在目标3中，将确定感染一种常见的肠道寄生虫对口腔TSE发病的影响。这些数据将为感染胃肠道病原体如何影响TSE易感性提供预测。目的探讨胃肠道病原体感染对口腔TSE发病的影响。目前，对TSE疾病缺乏有效的治疗和预防措施。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风险的确定、临床前诊断和治疗的发展，特别是TSE特异性黏膜疫苗的开发。

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.