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Role of distinct mononuclear phagocyte subsets in oral prion disease pathogenesis

不同的单核吞噬细胞亚群在口腔朊病毒病发病机制中的作用

基本信息

批准号：
BB/S005471/1
负责人：
Neil Mabbott
金额：
$ 59.54万
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：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FS005471%2F1
关键词：
Role distinct mononuclear phagocyte subsets

项目摘要

This project aims to determine the role of distinct mononuclear phagocyte (MNP) subsets in the establishment of oral prion infections. Prions cause fatal neurodegenerative diseases that affect animals and humans to which there are no cures. Prion diseases may also cause zoonoses, exerting high societal and economic costs. Many prion diseases, including natural sheep scrapie, bovine spongiform encephalopathy (BSE), chronic wasting disease (CWD) in deer and elk, and variant Creutzfeldt-Jakob disease (vCJD) in humans can be orally acquired. After ingestion of prion-contaminated food, the prions replicate first within the gut-associated lymphoid tissues (GALT) in the intestine as they make their journey from the gut to the brain. Prion replication within the GALT is essential for the establishment of prion disease after oral exposure. The prions then spread from the GALT via peripheral nerves in the intestine, then spread via the spinal cord and vagus nerve to the brain where they cause damage to nerve cells and death. The route by which orally-acquired antigens (Ag) and prions are initially delivered to the GALT is unclear. We have shown that prions "hi-jack" cells of the immune system in order to infect the body. The prions are initially transported across the gut epithelium into Peyer's patches by specialised gut epithelial cells known as M cells. Our data also suggest that the prions are then taken up by MNP which they appear to use as "Trojan horses" to carry them into the GALT. However, whereas some MNP appear aid prion infection in the GALT, others appear to play a host-protective role by engulfing and destroying the prions. We have shown that treatments that prevent the initial replication of prions within the GALT can block prion disease transmission. Thus, a thorough understanding of the role of MNP in oral prion disease pathogenesis will reveal the MNP subsets which enhance susceptibility by aiding the uptake of prions from the intestine. This work will also help identify MNP subsets which help to clear the prions from the body, and which could be potentially targeted to provide protection against oral prion infections.The main aims and hypotheses of this project are:1. To determine whether specific MNP subsets play an important role in the uptake of prions from the intestine and delivery their into the GALT2. To determine whether specific MNP subsets act to protect the body during prion disease by aiding the clearance of orally-acquired prions3. To determine whether oral prion disease susceptibility is increased in the presence of greater numbers of MNP in the intestineAs MNP have many important roles in immunity, immunopathology and homeostasis in the intestine, this work will have wide-ranging impact. A greater understanding of the role of distinct MNP subsets in antigen sampling within the GALT will help inform the design of novel adjuvants to improve the mucosal vaccine efficacy. No effective therapies are available to treat prion diseases. A greater understanding of the factors that influence oral prion disease susceptibility will enhance our understanding of those that influence the risk of disease transmission and help identify novel targets for intervention in these devastating and currently untreatable diseases.

该项目旨在确定不同的单核吞噬细胞（MNP）亚群在建立口腔朊病毒感染中的作用。朊病毒引起致命的神经退行性疾病，影响动物和人类，目前还没有治愈方法。朊病毒疾病还可能引起人畜共患病，造成高昂的社会和经济代价。许多朊病毒疾病，包括天然绵羊瘙痒症、牛海绵状脑病（BSE）、鹿和麋鹿的慢性消耗性疾病（CWD）以及人类的变异型克雅氏病（vCJD）都可以通过口服获得。在摄入朊病毒污染的食物后，朊病毒首先在肠道内的肠道相关淋巴组织（GALT）内复制，因为它们从肠道到大脑。朊病毒在GALT内的复制对于口服暴露后朊病毒疾病的建立是必不可少的。朊病毒然后从GALT通过肠道中的外周神经传播，然后通过脊髓和迷走神经传播到大脑，在那里它们导致神经细胞损伤和死亡。口服获得性抗原（Ag）和朊病毒最初传递到GALT的途径尚不清楚。我们已经证明朊病毒“劫持”免疫系统的细胞，以感染人体。朊病毒最初通过称为M细胞的专门的肠上皮细胞穿过肠上皮进入派尔集合淋巴结。我们的数据还表明，朊病毒随后被MNP吸收，它们似乎将MNP用作“特洛伊木马”，将朊病毒带入GALT。然而，尽管一些MNP似乎有助于GALT中的朊病毒感染，但其他MNP似乎通过吞噬和破坏朊病毒而发挥宿主保护作用。我们已经证明，阻止朊病毒在GALT内初始复制的治疗方法可以阻断朊病毒疾病的传播。因此，深入了解MNP在口腔朊病毒疾病发病机制中的作用将揭示MNP亚群通过帮助从肠道摄取朊病毒而增强易感性。这项工作也将有助于识别MNP亚群，这些亚群有助于清除体内的朊病毒，并可能成为预防口腔朊病毒感染的潜在靶点。确定特定的MNP亚群是否在从肠道摄取朊病毒并将其递送到GALT 2中起重要作用。确定特定的MNP亚群是否通过帮助清除口腔获得性朊病毒3来保护朊病毒疾病期间的身体。由于MNP在免疫、免疫病理学和肠道内稳态中具有许多重要作用，因此本工作将产生广泛的影响。更深入地了解不同的MNP亚群在GALT内抗原采样中的作用将有助于设计新的佐剂以提高粘膜疫苗的效力。没有有效的疗法可用于治疗朊病毒疾病。对影响口腔朊病毒病易感性的因素有更深入的了解，将增强我们对影响疾病传播风险的因素的理解，并有助于确定干预这些毁灭性和目前无法治愈的疾病的新靶点。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis.

DOI：
10.3390/ijms21197299
发表时间：
2020-10-02
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Mabbott NA;Bradford BM;Pal R;Young R;Donaldson DS
通讯作者：
Donaldson DS

Microglia deficiency accelerates prion disease but does not enhance prion accumulation in the brain.

DOI：
10.1002/glia.24244
发表时间：
2022-11
期刊：
GLIA
影响因子：
6.2
作者：
Bradford, Barry M.;McGuire, Lynne, I;Hume, David A.;Pridans, Clare;Mabbott, Neil A.
通讯作者：
Mabbott, Neil A.

Microglia deficiency accelerates prion disease but does not enhance prion accumulation in the brain

小胶质细胞缺乏会加速朊病毒疾病，但不会增强大脑中朊病毒的积累