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

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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.