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Novel strategies to detect and eliminate persistent Mycobacterium tuberculosis - applications in a murine Cornell model

检测和消除持久性结核分枝杆菌的新策略——在小鼠康奈尔模型中的应用

基本信息

批准号：
MR/P011144/1
负责人：
Yanmin Hu
金额：
$ 19.76万
依托单位：
St George's, University of London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FP011144%2F1
关键词：
Novel strategies detect eliminate persistent

项目摘要

Tuberculosis is a curable disease but still remains one of the biggest killers in the world. It kills nearly 2 million people worldwide every year and 98% of tuberculosis deaths are in the developing world affecting mostly young adults in their productive years. A quarter of a million tuberculosis deaths are also infected with HIV which weakens human immune systems, most of these people are in Africa. Tuberculosis especially affects the most vulnerable populations including children, the poorest and malnourished. Tuberculosis is caused by the bacterium called Mycobacterium tuberculosis. One important characteristics of this disease is that the bacterium has an unusual ability to grow and survive for extended periods of time in human body. Therefore, it has been estimated that 2 billion people, equal to one third of the world's total population, are infected with the bacterium in whom it causes unnoticeable latent infection that gives rise to a 5-10% lifetime risk of active tuberculosis. These persistent bacteria cannot be cultured using standard microbiological methods and are not killed by the current tuberculosis drugs. Therefore, tuberculosis treatment needs at least 6 months with four drugs to cure the patients. This long-term treatment is extremely difficult to implement especially in developing countries because of lack of affordability in both patients and healthcare services and limited infrastructure. It is important that treatment duration is shortened using effective tuberculosis drugs as it will significantly reduce patient suffering, side effect and expenses incurred by both patients and their families. In addition, shorter TB treatment duration may allow an earlier return of patients to their productive activities. The proposed research aims to identify and quantify those persistent bacteria in tuberculosis infected mice before and during treatment with new drugs to predict the outcome of tuberculosis treatment. The persistent bacteria will be "woken" by the addition of resuscitation promoting factors (RPFs) which are proteins produced by M. tuberculosis to restart growth. We have shown in our recent study that in mice there were persistent bacteria which depended on RPFs to grow. High-dose rifampicin which was added in the current treatment drug regimen was able to kill RPF-dependent persistent bacteria, as a result, treatment was cut short with no disease relapse. This meant that if we are able to remove RPF-dependent bacteria from patents, the treatment duration could be shortened with reduced relapse rate. In this proposal, we will apply the same principals and techniques which we have learnt from studying mice using a set of novel drug regimens to predict the outcome of human tuberculosis treatment, especially disease relapse. We will set up a model system in mice as a test bed to evaluate the potencies of new drug regimens before usage of them in much more expensive and time-consuming human testing.

结核病是一种可以治愈的疾病，但仍然是世界上最大的杀手之一。它每年在全世界造成近 200 万人死亡，98% 的结核病死亡发生在发展中国家，主要影响的是正值生产年龄的年轻人。一百万死于结核病的人中，有四分之一还感染了艾滋病毒，这种病毒会削弱人类的免疫系统，其中大多数人生活在非洲。结核病尤其影响最脆弱的人群，包括儿童、最贫困和营养不良的人群。结核病是由结核分枝杆菌引起的。这种疾病的一个重要特征是细菌具有一种不寻常的在人体内长时间生长和存活的能力。因此，据估计，有 20 亿人（相当于世界总人口的三分之一）感染了这种细菌，这种细菌会引起不明显的潜伏感染，导致终生患活动性结核病的风险为 5-10%。这些持久性细菌无法使用标准微生物学方法进行培养，也无法被当前的结核病药物杀死。因此，结核病治疗至少需要6个月的时间，四种药物才能治愈患者。这种长期治疗极其难以实施，特别是在发展中国家，因为患者和医疗服务缺乏负担能力，而且基础设施有限。使用有效的结核病药物缩短治疗时间非常重要，因为它将显着减少患者的痛苦、副作用以及患者及其家人产生的费用。此外，较短的结核病治疗时间可以使患者尽早恢复生产活动。拟议的研究旨在识别和量化新药治疗前和治疗期间结核感染小鼠体内的持久性细菌，以预测结核病治疗的结果。通过添加复苏促进因子（RPF），持久性细菌将被“唤醒”，复苏促进因子是结核分枝杆菌产生的蛋白质，可重新开始生长。我们在最近的研究中表明，小鼠体内存在依赖 RPF 生长的持久细菌。目前治疗药物方案中添加的大剂量利福平能够杀死RPF依赖性持久性细菌，从而缩短了治疗时间，且没有疾病复发。这意味着，如果我们能够从专利中去除 RPF 依赖性细菌，则可以缩短治疗时间并降低复发率。在这项提案中，我们将应用我们从研究小鼠中学到的相同原理和技术，使用一套新的药物方案来预测人类结核病治疗的结果，特别是疾病复发。我们将在小鼠中建立一个模型系统作为试验台，以评估新药物治疗方案的效力，然后再将其用于更昂贵和耗时的人体测试。