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Identification and characterization of Mycobacterium tuberculosis virulence genes involved in macrophage parasitism

Final Report Summary - TB-MACS (Identification and characterization of Mycobacterium tuberculosis virulence genes involved in macrophage parasitism)

Mycobacterium tuberculosis is a leading threat to human health, killing 40 000 people a week and causing 8 million new cases of disease every year. Current vaccination and chemotherapy strategies are unsatisfactory, making development of novel control strategies an important objective. Rational design of such strategies requires an understanding of the mechanisms by which M. tuberculosis is able to infect individuals and cause disease.

Central to the success of M. tuberculosis as a pathogen is an ability to replicate inside the normally destructive phagosomal compartments of macrophages. TB-MACS proposed to use innovative genetic screens to reveal the genetic and mechanistic basis of this characteristic. Specifically TB-MACS utilised a microarray based screening of an M. tuberculosis mutant library in two separate selections to identify mutants that are unable to inhibit phagosome acidification and / or unable to inhibit fusion of the phagosome with hydrolytic lysosomes. Mutants identified in these assays were isolated and characterised with respect to intracellular trafficking and growth in human macrophages. The in vivo phenotypes of the phagosome mutants were assessed in murine and guinea pig models of tuberculosis.

In order to begin to understand the mechanisms encoded by the mutated genes, TBMACS madea detailed examination of the proteomes and transcriptomes of selected mutants.

TB-MACS brought together three laboratories with complementary skills and facilities in high-throughput genetic screening, flow-cytometry, cell biology, transcriptomics and proteomics - the net result of which was a unique project that is able to provide system-wide answers to important unanswered questions about M. tuberculosis virulence. TB-MACS contributed to improving human health by defining bacterial products and processes that are essential to infection, and which will be useful in the rational development of new drugs and vaccines against tuberculosis. Information derived from the project will help identify novel drug targets for consideration in the development of chemotherapy strategies. Mycobacterial mutants generated during TBMACS may form the basis of novel attenuated vaccine strains.

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