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MILD-TB


HIV/AIDS

Immunogenicity of Mycobacterium Tuberculosis lipids in the Non Replicating Status of latency
Framework programme:
6
Call:
3
Project number:
LSHP-CT-2006-037326
EC contribution:
€ 1,099,794
Duration:
24 Months
Type:
STREP
Starting date:
December 2006

Keywords: Tuberculosis; latent infection; Antiretroviral Therapy; lipid antigen ; CD1 ; Vaccine

Summary:

Tuberculosis (TB) is a disease in which traditional prophylactic approaches have been largely unsuccessful. A search for new therapeutic interventions is required in order to overcome the low compliance to complex chemo-antibiotic regimens and to avoid multidrug resistance.

The aim of this project is to produce new knowledge and insight that bear potential for new therapeutic or prophylactic interventions. Project partners will be 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. This represents advancement beyond the current state of knowledge, which is limited to proteins synthesized during dormancy. The immune response against mycobacterial lipid antigens represents an important mechanism of defence. 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 to 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 lipidantigens or on immune-modulation.

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