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

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具有挑战性的长期治疗方案的必要性的阻碍。卡介苗是唯一可用的疫苗，对结核病的表现只提供了部分保护。众所周知，蠕虫寄生虫可以极化和抑制免疫反应，并可能限制对结核病的保护性免疫，例如由卡介苗接种引起的。在最初的资助期间，我们证明了永久曼索氏菌，一种以前被广泛忽视的丝状线虫，在加纳和喀麦隆广泛分布。在Perstans上发现了Wolbachia内共生菌，加纳首次对M.perstans进行了全面的研究，表明迄今未知的库蚊媒介物种。我们检测到了感染持久分枝杆菌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，我们调查了结核病特异性免疫病理学，并确定了结核病疾病和康复的有前景的替代生物标记物。最后，我们建立了以多西环素为基础的治疗永久分枝杆菌感染的方法，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Perstans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康复。下一个项目期的主要目标是：i)寻找新的Perstans媒介物种并表征生态媒介生态位；ii)表征Perstans对加纳和喀麦隆结核病表现和康复的影响；iii)确定Perstans感染对与结核病患者密切接触的卡介苗接种儿童预防结核病进展的影响。与结核病患者密切接触的儿童面临最高的结核分枝杆菌感染和发展为结核病的风险。因此，我们将招募与传染性结核病指数病例有密切接触的健康卡介苗接种儿童(n=2000)。儿童将被确定为永久分枝杆菌感染的特征，并将被跟踪一年，以确定永久分枝杆菌阳性和阴性组中结核病的进展率和严重程度。此外，将对感染或不感染永生化支原体的结核病患者进行疾病严重程度的表征，并将监测三个月，以确定在治疗下的有效康复。从最初的项目阶段确定的候选免疫生物标志物将被分析其预测价值。这是一个全面的方法，以确定永久分枝杆菌感染对疫苗诱导的保护和结核病疾病表现的生物学意义。这一结果可能导致通过多西环素治疗控制永久分枝杆菌的新建议，并可能有助于确定蠕虫合并感染对卡介苗预防结核病效果有限的影响。

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.