Determining the role of M cells in TSE agent neuroinvasion from the intestine

传染性海绵状脑病（tse）是一种导致大脑广泛变性的长期性疾病。在没有治疗方法的情况下，这些疾病总是致命的。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、骡子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被TSE剂污染的食物后，或通过皮肤、粘膜或角膜的病变或割伤而感染这些疾病。关于传染性TSE病原体从暴露部位（如皮肤损伤）到大脑的途径仍有许多疑问，在那里它会对神经细胞造成损害。暴露后，TSE病原体似乎会在免疫系统中复制，然后扩散到大脑。免疫系统中的这种复制对于TSE病原体有效到达大脑至关重要，并最终导致宿主神经损伤和死亡。我们的研究表明，在口腔感染后，TSE药物靶向肠道内的Peyer's斑块并感染称为滤泡树突状细胞的专门细胞。在TSE疾病期间，身体无法识别和破坏TSE因子。相反，滤泡树突状细胞被高水平的TSE试剂感染。我们的研究表明，TSE药物感染滤泡树突状细胞是疾病过程中至关重要的早期步骤，因为阻断TSE感染滤泡树突状细胞的治疗可以阻断疾病的传播。TSE制剂最初如何感染Peyer’s斑块及其内的滤泡树突状细胞尚不清楚。如果我们能发现TSE因子是如何感染这些部位的，我们或许就能设计出阻断这种能力的治疗方法，从而预防感染。肠道内壁的作用是防止病原微生物感染宿主。然而，在它里面有一种被称为M细胞的特殊细胞，它使免疫系统能够对肠道内容物进行取样，并在必要时发动免疫反应。虽然M细胞是肠道免疫系统的重要组成部分，但它们也可能是致命的，因为一些病原体似乎利用它们进入宿主。事实上，一些病原体，如沙门氏菌，可能利用M细胞作为特洛伊木马进入人体。这项研究将验证这样的假设，即TSE药物同样利用M细胞进入Peyer’s斑块并感染滤泡树突状细胞。如果我们能确定TSE病原体感染宿主的细胞途径，就有可能设计出阻断疾病传播的治疗方法。目前，缺乏有效的治疗和预防措施来治疗TSE疾病。此外，没有可靠的临床前诊断测试。因此，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，特别是开发针对TSE病原体的疫苗。

Transmissible spongiform encephalophathies (TSEs) are prolonged diseases which cause extensive degeneration in the brain. In the absence of a cure these 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 lesions or cuts to the skin, mucous membranes or cornea. Many questions remain concerning the route the infectious TSE agent takes from the site of exposure (eg: skin lesions) to the brain where it causes damage to nerve cells. After exposure TSE agents appear to high-jack the immune system where they replicate in it before they then spread to the brain. This replication in the immune system is crucial for TSE agents to efficiently reach the brain where they ultimately cause nerve damage and death of the host. Our studies show that after oral infection TSE agents target the Peyer's patches within the intestine and infect specialised cells, termed follicular dendritic cells. During TSE disease the body is unable to recognise and destroy the TSE agents. Instead, the follicular dendritic cells become infected with high levels of TSE agents. Our research shows that the infection of follicular dendritic cells by TSE agents is a crucial early step in the disease process as treatments that block TSE infection of follicular dendritic cells, block disease transmission. How TSE agents initially infect Peyer's patches and the follicular dendritic cells within them is unknown. If we can discover how TSE agents infect these sites, we may be able to design treatments that block this ability and therefore prevent infection. The lining of the intestine is designed to prevent pathogenic microorganisms infecting the host. However, within it are specialised cells termed M cells which enable the immune system to sample the gut contents and mount an immune response if necessary. While M cells are an important component of the intestinal immune system they may also be an Achilles heal as some pathogens appear to exploit them to enter the host. Indeed some pathogens such as Salmonella may use M cells as Trojan horses to enter the body. This study will test the hypothesis that TSE agents likewise exploit M cells to gain access to Peyer's patches and infect follicular dendritic cells. If we can identify the cellular route through which TSE agents infect the host it may be possible to design treatments that block disease transmission. Currently, effective therapeutics and prophylactics to treat TSE diseases are lacking. Furthermore, no reliable preclinical diagnostic test is available. Thus 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 vaccines against TSE agents.