"Mycobacterial diseases, like tuberculosis and leprosy, are still a threat for public health. Although antibiotherapy and BCG vaccine exist, they have failed to control these diseases. It is hence crucial to improve our knowledge of the factors involved in mycobacterial pathogenesis to design new therapies. The hallmark of mycobacterial pathogens is their ability to persist in the host by delaying the adaptive immune response. Among the mycobacterial factors suspected to play a role are phenolic glycolipids (PGL), which are produced notably by the major mycobacterial pathogens, including M. tuberculosis and M. leprae. PGL possess a common lipid core and species-specific saccharidic domains. However, the definitive proof of their role on immunomodulation is missing. In this project, I intend to investigate this issue and to identify the mechanism of action of PGL. I plan to use a novel strategy developed in the host laboratory based on the reprogramming of a biosynthetic pathway in BCG to make it synthesize species-specific PGL and to compare them in a similar relevant envelope. Using this tool, PGL from M. leprae was found to endow BCG with an increased capacity to exploit complement receptor CR3 for efficient invasion of phagocytes and evasion of inflammatory responses. To get insight into the structural basis, I propose to use a chemistry approach in which the various species-specific domains will be synthesized. The strength of this project is to combine my expertise in cellular microbiology with powerful approaches (recombinant BCG strains and synthetic PGL) to: 1) unravel the molecular mechanism of the interaction PGL-CR3 and its specificity by using different ligands; 2) identify other receptors for PGL; and 3) determine the signalling pathways involved in the immunomodulation by PGL. Besides to advance our understanding of the pathogenesis of major human diseases, I expect this work to open avenues for development of therapies against mycobacterial diseases."
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