Structures, functions and mechanisms of action of major M. tuberculosis and M. bovis protein virulence factors: a detailed understanding of the molecular basis of tuberculosis pathogenesis and importance of pathogen to host (360G-Wellcome-080085_Z_06_Z)

Tuberculosis remains the most significant bacterial infection of humans, leading to over 2 million deaths annually. The recent availability of complete genomes for M. tuberculosis and several closely related mycobacterial pathogens has catalysed work on the molecular basis of tuberculosis pathogenesis, resulting in the identification of a significant number of novel proteins clearly linked to virulence. The overall aim of the proposed programme is to obtain a detailed molecular understanding of the roles and mechanisms of action of major M. tuberculosis and M. bovis protein virulence factors, with a particular emphasis on secreted proteins involved in pathogen to host cell signalling. The proposed work will focus on three related areas: i) Continued investigation of the precise roles and mechanisms of action of the CFP-10.ESAT-6 complex and MPB70, with key goals including identification of host cell receptors and assessment of the importance of specific signalling pathways in mediating host cell responses. ii) Characterisation of the structures, functions and mechanisms of action of other members of the ESAT-6/CFP-10 family, such as Rv0287/Rv0288, with key aims including identification of host cell target proteins and determination of the rules governing complex formation. iii) Determination and analysis of high resolution structures for the novel proteins encoded by the Rv3613c-Rv3616c operon, with key goals including the identification and assessment of possible functional sites and mechanisms of action.