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

确定 M 细胞在 TSE 制剂肠道神经侵袭中的作用

基本信息

批准号：
BB/J014672/1
负责人：
Neil Mabbott
金额：
$ 48.51万
依托单位：
University of Edinburgh
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FJ014672%2F1
关键词：
Determining role cells TSE agent

项目摘要

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.

传染性海绵状脑病（TSE）是一种长期的疾病，导致广泛的变性，在大脑中。这些疾病如无治疗方法，无一例外都是致命的.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瘙痒症。一些动物物种和人类在食用了被TSE病原体污染的食物后，或通过皮肤、粘膜或角膜的损伤或割伤而感染这些疾病。关于传染性TSE因子从暴露部位（例如：皮肤病变）到大脑的途径仍然存在许多问题，在大脑中它会对神经细胞造成损伤。暴露后，TSE因子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试剂有效到达大脑至关重要，在那里它们最终导致宿主的神经损伤和死亡。我们的研究表明，在口服感染后，TSE试剂靶向肠道内的派尔集合淋巴结并感染称为滤泡树突细胞的专门细胞。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因子感染。我们的研究表明，TSE因子对滤泡树突状细胞的感染是疾病过程中至关重要的早期步骤，因为阻断滤泡树突状细胞的TSE感染的治疗阻断了疾病传播。TSE病原体最初如何感染派尔集合淋巴结和其中的滤泡树突状细胞尚不清楚。如果我们能发现TSE病原体如何感染这些部位，我们就可能设计出阻断这种能力的治疗方法，从而预防感染。肠道内壁的设计是为了防止病原微生物感染宿主。然而，在它里面是被称为M细胞的专门细胞，使免疫系统能够对肠道内容物进行采样，并在必要时产生免疫反应。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弱点，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，可能会利用M细胞作为特洛伊木马进入人体。这项研究将测试的假设，TSE代理同样利用M细胞获得访问派尔集合淋巴结和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。因此，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，特别是开发针对TSE病原体的疫苗。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Characterisation of a novel Fc conjugate of macrophage colony-stimulating factor.

DOI：
10.1038/mt.2014.112
发表时间：
2014-09
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
0
作者：
Gow DJ;Sauter KA;Pridans C;Moffat L;Sehgal A;Stutchfield BM;Raza S;Beard PM;Tsai YT;Bainbridge G;Boner PL;Fici G;Garcia-Tapia D;Martin RA;Oliphant T;Shelly JA;Tiwari R;Wilson TL;Smith LB;Mabbott NA;Hume DA
通讯作者：
Hume DA

Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility.

DOI：
10.1371/journal.ppat.1006075
发表时间：
2016-12
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Donaldson DS;Sehgal A;Rios D;Williams IR;Mabbott NA
通讯作者：
Mabbott NA

The functional maturation of M cells is dramatically reduced in the Peyer's patches of aged mice.

DOI：
10.1038/mi.2012.141
发表时间：
2013-09
期刊：
MUCOSAL IMMUNOLOGY
影响因子：
8
作者：
Kobayashi, A.;Donaldson, D. S.;Erridge, C.;Kanaya, T.;Williams, I. R.;Ohno, H.;Mahajan, A.;Mabbott, N. A.
通讯作者：
Mabbott, N. A.

The Gut-Associated Lymphoid Tissues in the Small Intestine, Not the Large Intestine, Play a Major Role in Oral Prion Disease Pathogenesis.