Tuberculosis is a disease in which traditional prophylactic approaches have been largely unsuccessful. The search for new therapeutic interventions is required to overcome the low compliance to complex chemo-antibiotic regimens and to avoid multi-drug resistance. Aim of this project is to produce new knowledge and insight that bear a potential for new therapeutic or prophylactic interventions focusing on one of the most critical immune evasion mechanism of Mycobacterium tuberculosis (Mtb): the capacity to switch to a dormant status of latency, which causes its persistence in the host. The switch implies a reduction/abrogation of the synthesis of antigens required for activation of T lymphocytes primed in the early phase of infection, while new products are generated with possible antigenic properties. MILD-TB will analyse the variations in lipid metabolism and composition associated to dormancy. The immune response against mycobacterial lipid antigens represents an important mechanism of defense. However, no data are available on the antigenicity of lipids produced by dormant Mtb. MILD-TB will analyse the immunogenicity of lipids isolated from non replicating Mtb produced in vitro using a culture method resembling Mtb dormancy in vivo. Lipids will be analysed in reference strains and clinical isolates from endemic areas and will be compared with those produced by replicating Mtb. The immunogenicity of lipids specifically isolated from dormant Mtb will be determined using pre-existing and newly established lipid-specific T cell clones and by immunizing CD1b transgenic mice. Parallel analysis of susceptibility of dormant Mtb to T-dependent mechanisms of direct or indirect killing will be performed to explore the possibility of new therapeutic or prophylactic interventions based on vaccination with lipid-antigens or on immune-modulation.
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