Evaluation of a novel microbiological diagnostic test for latent tuberculosis infection in Ethiopia (Micro-LTBI)

埃塞俄比亚潜伏性结核感染新型微生物诊断测试（Micro-LTBI）的评估

• 批准号: MR/P024548/1
• 负责人: Adrian Martineau
• 金额: $ 48.98万
• 依托单位: Queen Mary 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%2FP024548%2F1
• 关键词: Evaluation; novel; microbiological; diagnostic; test

Tuberculosis (TB) is a bacterial infectious disease. It causes 1.5 million deaths each year, 95% of which occur in low- and middle-income countries (LMICs). The disease particularly affects young adults, with adverse consequences for economic growth. In many LMICs, this problem is compounded by the problem of TB in cattle (bovine TB). This 'double-hit' is a particular problem in Ethiopia, which has the tenth highest burden of human TB in the world: bovine TB is widespread (prevalence 5-30%) and the country's economy is highly dependent on cattle farming. Improved TB control in humans and cattle would significantly enhance economic growth and welfare in Ethiopia and other similarly-burdened LMICs.Most TB cases in humans arise when a dormant TB infection re-activates to cause disease. Dormant TB infection is very common in LMICs and this pool of infection will need to be treated if TB is ever going to be eliminated. Antibiotic treatment for dormant TB infection is effective, but roll-out of this treatment is limited by the lack of an accurate 'gold standard' diagnostic test for the condition. Existing tests for dormant TB infection rely on detecting an immune response to the bacteria, rather than detecting the bacteria itself. However, less than 10% of those with a positive immune test ever go on to develop active TB. This makes it difficult to target antibiotic treatment for dormant TB infection at the people who will benefit from it.This situation could be about to change: very recently, a team of researchers in Germany (one of whom is a co-applicant on this grant) has reported that they have been able to detect TB bacteria in the blood of people with dormant TB infection. The number of bacteria is very small, and quite a large amount of blood (100 ml) is needed in order to detect them reliably. This remarkable finding has been made in just seven people living in Europe. The next step is to run the new test in a larger group of people who live in a country where TB is widespread. To take this idea forward, we have forged a new collaboration between Ethiopian and British scientists who together have the exact combination of clinical and technical skills needed to evaluate this new test.We will carry out the following studies. First, we will recruit 200 healthy people who have recently been in contact with an infectious case of TB ('TB contacts') - 100 urban residents of Addis Ababa who have been exposed to a person with infectious lung TB living in their home, and 100 rural cattle herders who have been exposed to a cow suffering from bovine TB. We will run the new blood test in these TB contacts, and, where we find dormant TB bacteria in the blood stream, we will do genetic fingerprinting to see if the dormant bacteria found in the bloodstream are identical to those isolated from the case of infectious TB (human or bovine) to which they were exposed. If the genetic fingerprints of the TB bacteria are the same, this will suggest that detection of TB bacteria in the blood of people with dormant TB infection is very unlikely to be a 'chance finding'.We will also recruit 40 people who are about to start antibiotic treatment for dormant TB infection, and run the new test before and after treatment. If we find that the antibiotic treatment clears dormant TB bacteria from the blood stream, this would suggest an additional potential application for the new test: monitoring response to antibiotic treatment of dormant TB infection. This is important, because existing tests cannot tell if antibiotic treatment for dormant TB infection has been effective or not.Taken together, these studies will give us a clear idea as to whether the findings of the German team can be reproduced in a LMIC setting. If so, then we will apply for further funding to optimise the test to use smaller blood volumes, and conduct definitive studies to evaluate whether it could be integrated into existing TB control programmes in LMICs.

结核病（TB）是一种细菌性传染病。它每年导致150万人死亡，其中95%发生在低收入和中等收入国家（LMIC）。这种疾病特别影响年轻人，对经济增长产生不利影响。在许多中低收入国家，牛结核病问题（牛结核病）加剧了这一问题。这种“双重打击”是埃塞俄比亚的一个特殊问题，埃塞俄比亚的人类结核病负担在世界上排名第十：牛结核病很普遍（患病率5-30%），该国的经济高度依赖养牛业。改善人和牛的结核病控制将大大提高埃塞俄比亚和其他负担类似的中低收入国家的经济增长和福利。大多数人类结核病病例是在潜伏的结核病感染重新激活导致疾病时出现的。肺结核感染在中低收入国家非常常见，如果要消除肺结核，就需要治疗这种感染。抗生素治疗潜伏性结核感染是有效的，但由于缺乏准确的“金标准”诊断测试，这种治疗的推广受到限制。现有的休眠结核病感染检测依赖于检测对细菌的免疫反应，而不是检测细菌本身。然而，只有不到10%的免疫测试阳性的人会继续发展为活动性结核病。这使得针对潜伏性结核感染的抗生素治疗很难针对受益者。这种情况可能即将改变：最近，德国的一个研究小组（其中一位是该研究的共同申请人）报告说，他们已经能够在潜伏性结核感染者的血液中检测到结核细菌。细菌的数量非常少，需要相当大量的血液（100 ml）才能可靠地检测到它们。这一惊人的发现仅在欧洲的七个人身上发现。下一步是在一个结核病流行国家的更大人群中进行新的测试。为了推进这一想法，我们在埃塞俄比亚和英国科学家之间建立了一个新的合作关系，他们共同拥有评估这种新测试所需的临床和技术技能的确切组合。我们将开展以下研究。首先，我们将招募200名最近接触过结核病传染病例的健康人（“结核病接触者”）-- 100名阿迪斯的城市居民，他们在家中接触过患有传染性肺结核的人，100名农村牧民，他们接触过患有牛结核病的奶牛。我们将在这些结核病接触者中进行新的血液测试，如果我们在血液中发现休眠的结核病细菌，我们将进行遗传指纹分析，以确定血液中发现的休眠细菌是否与从他们接触的传染性结核病（人类或牛）中分离出来的细菌相同。如果结核菌的基因指纹是相同的，这将表明在潜伏结核病感染者的血液中检测到结核菌的可能性很小。我们还将招募40名即将开始对潜伏结核病感染进行抗生素治疗的人，并在治疗前后进行新的测试。如果我们发现抗生素治疗可以清除血液中的休眠结核菌，这将表明新测试的另一个潜在应用：监测对休眠结核感染抗生素治疗的反应。这一点很重要，因为现有的测试无法判断抗生素治疗休眠结核感染是否有效。综合考虑，这些研究将使我们清楚地了解德国团队的发现是否可以在LMIC环境中重现。如果是这样的话，我们将申请进一步的资金来优化测试，使用更小的血液体积，并进行确定性的研究，以评估它是否可以整合到现有的结核病控制计划中LMIC。

项目成果

Epidemiology of Bovine Tuberculosis and Its Zoonotic Implication in Addis Ababa Milkshed, Central Ethiopia.

• DOI: 10.3389/fvets.2021.595511
• 发表时间: 2021
• 期刊: Frontiers in veterinary science
• 影响因子: 3.2
• 作者: Tulu B;Zewede A;Belay M;Zeleke M;Girma M;Tegegn M;Ibrahim F;Jolliffe DA;Abebe M;Balcha TT;Gumi B;Martineau HM;Martineau AR;Ameni G
• 通讯作者: Ameni G

Detection of Mycobacterium tuberculosis complex DNA in CD34-positive peripheral blood mononuclear cells of asymptomatic tuberculosis contacts: an observational study.

在无症状的结核病接触的CD34阳性外周血单核细胞中检测结核分枝杆菌复合物DNA：一项观察性研究。

• DOI: 10.1016/s2666-5247(21)00043-4
• 发表时间: 2021-06
• 期刊: The Lancet. Microbe
• 作者: Belay M;Tulu B;Younis S;Jolliffe DA;Tayachew D;Manwandu H;Abozen T;Tirfie EA;Tegegn M;Zewude A;Forrest S;Mayito J;Huggett JF;Jones GM;O'Sullivan DM;Martineau HM;Noursadeghi M;Chandran A;Harris KA;Nikolayevskyy V;Demaret J;Berg S;Vordermeier M;Balcha TT;Aseffa A;Ameni G;Abebe M;Reece ST;Martineau AR
• 通讯作者: Martineau AR

Cellular and Cytokine Responses in the Granulomas of Asymptomatic Cattle naturally infected with Mycobacterium bovis in Ethiopia

埃塞俄比亚自然感染牛分枝杆菌的无症状牛肉芽肿的细胞和细胞因子反应

• DOI: 10.1101/2020.06.12.149518
• 发表时间: 2020
• 作者: Tulu B

Detection of M. tuberculosis DNA in TB contacts' PBMC does not associate with blood RNA signatures for incipient tuberculosis

结核病接触者 PBMC 中结核分枝杆菌 DNA 的检测与早期结核病的血液 RNA 特征无关

• DOI: 10.1101/2023.09.26.23296131
• 发表时间: 2023
• 作者: Rosenheim J

Toward a molecular microbial blood test for tuberculosis infection

• DOI: 10.1016/j.ijid.2024.106988
• 发表时间: 2024-04-01
• 期刊: INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES
• 影响因子: 8.4
• 作者: Martineau，Adrian R.;Chandran，Shruthi;Tiwari，Divya
• 通讯作者: Tiwari，Divya