Effect of HIV infection on the function of CD8+ polycytotoxic T lymphocytes in human tuberculosis

结核病仍然是人类的主要负担，每年新增病例近1000万例，死亡150万人。在德国，2019年报告的新增病例超过5000例。除了是一种可传播的疾病外，耐药菌株、肺外疾病和难民病例管理的日益频繁也是新出现的问题。为了开发新的结核病治疗和预防策略，提高我们对引起疾病的病原体--细胞内结核分枝杆菌的免疫反应的了解是至关重要的。T淋巴细胞是支持感染巨噬细胞抗分枝杆菌效应功能的关键分子。T细胞功能受损，如免疫抑制治疗、严重糖尿病或高龄，会增加发病风险。特别是在撒哈拉以南非洲，感染人类免疫缺陷病毒(艾滋病毒)是一个危险因素，因为它干扰了T细胞的功能。在世界这一地区，大多数结核病患者同时感染艾滋病毒。因此，为了在消除结核病的道路上发展新的概念，了解这两种微生物病原体的相互作用至关重要。在这个项目中，我们将比较结核病患者、HIV患者和混合感染者的T细胞功能。马拉维布兰太尔的基础设施和流行病学是进行这些实验的理想地点。当地的研究中心在建立临床研究方面拥有长期的经验，这些研究涉及对从支气管肺泡灌洗中获得的细胞进行免疫学分析。此外，结核病患者合并感染艾滋病毒的比率超过70%。免疫学研究的重点将是T淋巴细胞亚群，它识别和破坏感染结核分枝杆菌的巨噬细胞，并同时杀死病原体。这些CD8+T淋巴细胞共表达穿孔素、颗粒溶素和颗粒酶B等溶解和抗微生物分子，被称为“多细胞毒T细胞”。乌尔姆大学的研究小组最近发现了这一人群，初步发现多细胞毒性T细胞在结核病的病程中具有有益的作用。总而言之，这个非洲和德国的研究合作的目的是调查艾滋病毒感染对人类结核病中多细胞毒性T细胞频率和功能的影响。从未来的角度来看，这些研究可能会为引入T细胞功能的药理学操作作为辅助治疗来补充传统的多药治疗结核病奠定科学基础。

Tuberculosis remains a major burden for mankind with close to 10 million new cases per year and 1.5 million fatalities. In Germany more than 5000 new cases were reported in 2019. Besides being a transmissible disease, the increasing frequency of drug-resistant strains, extrapulmonary disease and the management of cases occurring in refugees are emerging issues. For the development of new strategies for the treatment and prophylaxis of tuberculosis it is critical to increase our understanding of the immune response against the intracellular bacterium Mycobacterium tuberculosis, the causative agent of disease. T-lymphocytes are key players by supporting the antimycobacterial effector functions of infected macrophages. Impairment of T-cell function, e.g. by immunosuppressive therapy, severe diabetes or high age enhance the risk for developing. Especially in sub-Saharan Africa infection with the human immunodeficiency virus (HIV) is a risk factor by interfering with T cell functions. In this part of the world the majority of tuberculosis patients are co-infected with HIV. To develop novel concepts on the way of eliminating tuberculosis, it is therefore critical to understand the interaction of these two microbial pathogens. In this project we will compare the T cell functions in patients with tuberculosis, HIV or co-infected individuals. The infrastructure and epidemiology in Blantyre, Malawi is ideal to conduct these experiments. The local research center has a longstanding experience in setting up clinical studies involving the immunological analysis of cells obtained from the bronchoalveolar lavage. In addition the rate of tuberculosis patients co-infected with HIV exceeds 70%. The focus of the immunological studies will be a subpopulation of T-lymphocytes, which recognizes and destroys Mycobacterium tuberculosis-infected macrophages and concomitantly kills the pathogen. These CD8+ T lymphocytes co-express the lytic and antimicrobial molecules perforin, granulysin and granzyme B and have been termed “polycytotoxic T cells”. This population was recently identified by the team from Ulm and initial findings indicate that polycytotoxic T cells have a beneficial effect on the course of tuberculosis. Taken together, the aim of this African-German research collaboration is to investigate the effect of HIV-infection on the frequency and function of polycytotoxic T cells in human tuberculosis. As a future perspective, these studies may build the scientific backbone to introduce the pharmacological manipulation of T-cell function as an adjuvant treatment to complement conventional multi-drug treatment of tuberculosis.