MycoLipid – the interaction of mycobacterial lipids with the cellular immune system governs granuloma formation and maintenance

结核病是一个典型的单一健康问题。分枝杆菌（M.）结核病主要适应于人类。M.牛和山羊是密切相关的，但具有更广泛的宿主谱。它们感染人类和各种野生动物和牲畜。这种细菌在人类和动物中引起非常相似的疾病：慢性感染，其特征是肺和肠中的肉芽肿性病变。肉芽肿是对抗分枝杆菌的免疫防御的关键结构。免疫系统无法消除细菌。相反，它们通过高度动态的持续免疫过程被隔离在肉芽肿内。每当免疫力减弱时，这种防御机制就会崩溃，持续存在的细菌就会爆发，最终传播到新的宿主。已知分枝杆菌脂质，如phtiocerol dimyceroserate（PDIM）、甘露糖基化脂阿拉伯甘露聚糖（ManLAM）或海藻糖-二霉菌酸酯（TDM）通过激活先天免疫途径对于肉芽肿诱导是关键的。然而，需要T淋巴细胞来协调肉芽肿形成以获得成熟的保护结构。使用豚鼠作为一个小动物模型，独特地再现干酪坏死性TB肉芽肿的病理，我们已经证明了T细胞识别分枝杆菌脂质在MHC-ii和CD 1-限制的方式在致敏或卡介苗接种的动物的存在。根据文献和我们自己的观察，我们假设这些脂质反应性T细胞特别有助于成熟肉芽肿的形成和维持。使用我们小组为豚鼠感染模型开发的实验方法的设备，我们的目的是阐明哪些抗原是重要的，以及在这个过程中采用了哪些免疫效应途径。只有了解了免疫系统和病原体之间复杂的相互作用，才能设计出新的预防策略来防治人类和人畜共患结核病。

Tuberculosis is a prototypic One-Health problem. Mycobacterium (M.) tuberculosis is primarily adapted to humans. M. bovis and caprae are closely related, but have a broader host spectrum. They infect humans and a broad range of wildlife and livestock animals. The bacteria cause very similar diseases in humans and animals: chronic infections that are characterized by granulomatous lesions in the lung and intestine. Granulomas are the key structures in the immune defense against mycobacteria. The immune system is unable to eliminate the bacteria. Instead, they are walled off inside the granuloma through a highly dynamic ongoing immune process. Whenever immunity wanes this defense mechanism collapses and persisting bacteria break out to eventually transmit to a new host. It is known that mycobacterial lipids, such as phtiocerol dimycoceroserate (PDIM), mannosylated lipoarabinomannan (ManLAM) or trehalose-dimycolate (TDM) are pivotal for granuloma induction through the activation of innate immune pathways. However, T lymphocytes are required to orchestrate granuloma formation to obtain mature protective structures. Using the guinea pig as a small animal model that uniquely reproduces the pathology of the caseous necrotizing TB-granuloma, we have demonstrated the presence of T cells recognizing mycobacterial lipids in an MHC-ii and a CD1-restricted manner in sensitized or BCG-vaccinated animals. Based on literature and own observations we hypothesize that these lipid-reactive T cells particularly contribute to the formation and maintenance of the mature granuloma. Using the armamentarium of experimental approaches that has been developed in our group for the guinea pig infection model we aim to elucidate which antigens are important and which immune effector pathways are employed in this process. Only if the complex interaction between the immune system and the pathogen has been understood, novel prevention strategies can be devised to combat human and zoonotic tuberculosis.