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 Our unpublished data also suggest that these detrimental effects occur, at least in part, through changes in the immune cell's ability to control bacterial growth.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 cells, to better understand how it mediates its functions (particularly its role controlling mycobacterial growth) and the mechanisms by which this receptor induces these responses. We will define exactly what the receptor is recognising (its ligand) on the surface of mycobacterial cells. These experiments will reveal the cellular mechanisms employed by the receptor. We will also determine whether this receptor functions in a similar manner in human cells. We will determine the effect of small genetic changes (called polymorphisms) in the human gene encoding this receptor. Such changes may have significant effects on receptor function and alter disease susceptibility in human populations. To summarise, we have discovered a receptor that promotes susceptibility to tuberculosis, and the experiments described here will provide substantial insights into the role and functions of this molecule in both mice and humans. The information we obtain in this project will allow us to gain a much better understanding of how MTB causes infection and will provide important scientific advances that will enable us to develop better treatments for people in the future.

C-type lectin receptors (CLR) trigger intracellular signalling cascades that induce a wide range of cellular and immunological responses which play critical protective roles in antimicrobial immunity. We recently discovered that one such CLR promotes susceptibility to, rather than protection against, infection with Mycobacterium tuberculosis (MTB), one of the world's deadliest bacterial infections. Our unpublished data suggest that this occurs, at least in part, through alterations in the host's ability to restrict mycobacterial replication. We therefore will elucidate the immunological, cellular and molecular mechanisms by which this CLR mediates its negative effects on anti-mycobacterial immunity. We will use receptor-deficient mice to determine the role of this receptor during infection with MTB, by characterising bacterial burdens, inflammation and other key immune parameters, including T-cell responses, over the course of infection. Using in vitro approaches, we will determine the impact of the receptor on a variety of key cellular responses, including antimicrobial mechanisms. We will also establish which signalling pathways are involved and identify the mycobacterial ligand recognised by the receptor. Furthermore, we will translate our findings to the human system. To achieve this we will establish the function of this receptor in primary and transfected human cells, and the impact of receptor polymorphisms known to affect its function. With collaborators, we will explore the possibility of an association between these polymorphisms and alterations in disease susceptibility in human populations. In sum, we have discovered a CLR that promotes susceptibility to infection with MTB. The experiments described here will provide substantial and definitive insights into the roles and functions of this molecule in both mice and humans.