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需要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，只能部分预防结核病的表现。蠕虫寄生虫是众所周知的寄生虫和抑制免疫反应，并可能会限制对结核病的保护性免疫，例如由BCG疫苗接种诱导的。在最初的资助期间，我们证明了曼森氏perstans，以前在很大程度上被忽视的丝虫线虫，是广泛分布在加纳和喀麦隆。在M. perstans和第一综合M.在加纳进行的持久性有机污染物研究表明，迄今为止，库蠓属媒介物种未知。我们检测到M perstans感染特异性的免疫极化和免疫调节，调节免疫反应对分枝杆菌疾病。此外，我们研究了结核病特异性免疫病理学，并确定了结核病和恢复的有希望的替代生物标志物。最后，我们建立了以强力霉素为基础的治疗M。perstans感染和宿主免疫应答中确定的治疗依赖性变化。基于这些结果，我们假设M. perstans感染会透过调节保护性免疫力而削弱卡介苗接种的效力，并影响结核病的表现和康复。perstans媒介物种和生态特征向量生态位; ii）表征M. perstans对加纳和喀麦隆结核病表现和恢复的影响; iii）确定M.持久性结核杆菌感染对预防结核病患者密切接触的卡介苗接种儿童的结核病进展的作用。与结核病患者密切接触的儿童面临最高的M风险。结核病感染和发展结核病。因此，我们将招募与传染性结核指标病例密切接触的健康卡介苗接种儿童（n=2000）。儿童将被描述为M。perstans感染，并将随访一年，以确定结核病的进展率和严重程度内M。perstans阳性和阴性组。此外，无论是否存在M.将对持久性有机污染物感染的疾病严重程度进行表征，并将监测三个月，以确定在治疗下的有效恢复。从项目初期鉴定的免疫生物标志物候选者将被分析其预测价值。持久性结核杆菌感染对结核病疫苗诱导保护和疾病表现的影响。这些结果可能会导致新的建议M。这可能有助于确定蠕虫合并感染对卡介苗接种预防结核病的有限效力的影响。

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.