Mansonella perstans effects on BCG vaccine-induced protection against childhood tuberculosis as well as tuberculosis disease severity and recovery in Ghana and Cameroon

加纳和喀麦隆的持久曼森氏菌对卡介苗疫苗诱导的儿童结核病保护以及结核病严重程度和恢复的影响

• 批准号: 405027271
• 负责人: Professor Dr. Achim Hoerauf
• 金额: --
• 依托单位: Department of Medicine
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/405027271?language=en
• 关键词: Mansonella; perstans; effects; BCG; vaccine

Tuberculosis (TB) is one of the most distressing infectious diseases causing more than 1.5 millions deaths per year. Control of TB is largely impeded by the lack of an effective vaccine and the necessity of a challenging long-term treatment regimen. BCG, the only available vaccine, provides only partial protection against TB manifestations. Helminth parasites are well known to polarize and suppress immune responses and may constrain protective immunity against TB e.g. induced by BCG vaccination.In the initial funding period we demonstrated that Mansonella perstans, a previously largely neglected filarial nematode, is widely distributed in Ghana and Cameroon. Wolbachia endosymbionts were found on M. perstans and first comprehensive M. perstans studies in Ghana suggested so far unknown Culicoides vector species. We detected M. perstans infection specific immune polarization and immune regulation, which modulated immune responses against mycobacterial diseases. Furthermore, we investigated TB-specific immune pathology and identified promising surrogate biomarkers of TB disease and recovery. Finally, we established doxycycline-based treatment of M. perstans infection and identified treatment-dependent changes in host immune responses. Based on these results, we hypothesize that M. perstans infection impairs the efficacy of BCG vaccination by modulating protective immunity and affects TB disease manifestation and recovery.The main aims of the next project period are to i) identify novel M. perstans vector species and characterize ecological vector niches; ii) characterize M. perstans effects on TB disease manifestation and recovery in Ghana and Cameroon; iii) determine the effect of M. perstans infection on prevention of TB progression of BCG vaccinated children with close TB patient contact. Children that are in close contact to TB patients face the highest risk of M. tuberculosis infection and of developing TB disease. Therefore, we will recruit healthy BCG-vaccinated children (n=2000) with close contact to an infectious TB index case. Children will be characterized for M. perstans infection and will be followed for one year to determine TB disease progression rates and severity within M. perstans positive and negative groups. In addition, TB patients with or without M. perstans infection will be characterized for disease severity and will be monitored for three months to determine efficient recovery under therapy. Immune biomarker candidates identified from the initial project period will be analysed for their predictive value.This is a comprehensive approach to determine the biological significance of M. perstans infection on vaccine induced protection and disease manifestation in TB. The results may lead to novel recommendations for M. perstans control by doxycycline treatment and may help to determine the impact of helminth co-infection on the limited efficacy of BCG vaccination for protection against TB.

结核病是最令人痛苦的传染病之一，每年造成150多万人死亡。结核病的控制在很大程度上受到缺乏有效疫苗和必须采用具有挑战性的长期治疗方案的阻碍。卡介苗是唯一可用的疫苗，对结核病的表现只能提供部分保护。众所周知，寄生虫会分化和抑制免疫反应，并可能抑制对结核病的保护性免疫，例如由卡介苗疫苗诱导的免疫。在最初的资助期内，我们证明了一种以前基本上被忽视的丝状线虫——永久曼索菌在加纳和喀麦隆广泛分布。在波斯人身上发现了沃尔巴克氏体内共生菌，在加纳对波斯人进行的首次综合研究表明，迄今为止未知的库蠓病媒物种。我们检测到了波斯分枝杆菌感染的特异性免疫极化和免疫调节，它们调节了对分枝杆菌疾病的免疫反应。此外，我们研究了结核病特异性免疫病理学，并确定了有希望的结核病疾病和康复的替代生物标志物。最后，我们建立了以多西环素为基础的波斯人感染治疗方法，并确定了宿主免疫反应的治疗依赖性变化。基于这些结果，我们假设波斯分枝杆菌感染通过调节保护性免疫来削弱卡介苗接种的效果，并影响结核病的表现和恢复。下一个项目期的主要目标是：1)鉴定新的波斯坦病媒物种和表征生态病媒生态位；ii)描述持久性分枝杆菌对加纳和喀麦隆结核病表现和康复的影响；iii)确定卡介苗接种后与结核病患者密切接触的儿童感染结核菌对预防结核病进展的影响。与结核病患者密切接触的儿童感染结核分枝杆菌和发展为结核病的风险最高。因此，我们将招募与传染性结核病指数病例有密切接触的接种过bcg疫苗的健康儿童（n=2000）。将对儿童进行持久性分枝杆菌感染特征分析，并对其进行为期一年的随访，以确定持久性分枝杆菌阳性组和阴性组的结核病进展率和严重程度。此外，患有或不患有波斯分枝杆菌感染的结核病患者将根据疾病严重程度确定特征，并将进行三个月的监测，以确定治疗后的有效康复情况。从项目初始阶段确定的免疫生物标志物候选物将分析其预测价值。这是一种全面的方法来确定结核分枝杆菌感染在疫苗诱导保护和疾病表现方面的生物学意义。这一结果可能为通过强力霉素治疗控制结核分枝杆菌提供新的建议，并可能有助于确定寄生虫合并感染对卡介苗接种预防结核病的有限效果的影响。