Dectin-1-mediated suppression of protective anti-mycobacterial immunity

Despite over a century of research, tuberculosis remains one of the deadliest bacterial infections in humans, resulting in over one-and-a-half million deaths each year. The important tools for combatting this global problem are the development of new anti-tubercular drugs and a more effective vaccine. Both depend, in large part, on obtaining a better understanding of the interactions between the human 'host' body and this bacterial microbe. We previously found a molecule on the surface of immune cells that senses microbes and activates host immune responses. We call this type of molecule a receptor. Remarkably, our new data now suggest that rather than being beneficial, the actions of this receptor actually increase susceptibility to infection with the bacterium that causes tuberculosis, M. tuberculosis (MTB). Our unpublished data also suggest that these detrimental effects occur, at least in part, through changes in the immune cell's ability to control bacterial growth. This discovery provides vital new insights into the factors underlying susceptibility to tuberculosis. Therefore, we propose to determine how this receptor negatively influences the protective immune responses and the extent to which this impacts human disease.
To do this research, we will use experimental models of MTB infection in mice by comparing normal mice to mice which lack this receptor. We will examine important immune parameters that may be influenced by this receptor at different points during infection, and particularly after the immune system has had time to recognise and respond specifically to M. tuberculosis (known as the adaptive immune response). We will determine which receptor-expressing immune cells (or other cell types) play central roles in these responses. These experiments will allow us to understand how the receptor influences the immune response during infection. We will also use cell lines and tissue culture techniques to explore the role of this receptor in individual...