Characterisation of the C-type lectin receptor CLECSF8 (CLEC4D)

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Despite over a century of research, Mycobacterium tuberculosis remains one of the deadliest bacterial infections, resulting in over one and a half million deaths each year. Priorities to combat this global problem are the development of new antitubercular drugs and a more effective vaccine; both of which depend, in large part, on obtaining a better understanding of interactions between the host and this bacterial pathogen. We have identified a novel molecule (receptor) found on the surface of immune cells which appears to be involved in the control of M. tuberculosis during infection. Elucidating the functions of this receptor will provide substantial new insights into how the host combats these infections. To do this, we will make use of mouse models of infection by comparing normal mice to mice which lack this receptor. We will look at a variety of responses that may be influenced by the receptor, including how the host responds immediately upon infection (innate response) as well as responses later during infection, once the host has had time to recognise and respond specifically to M. tuberculosis (adaptive response). We will also look at the responses of individual cells to better understand how this receptor functions, such as inducing bacterial killing for example, and to determine what the receptor actually recognises on the mycobacteria, and the range of mycobacterial species that can be recognised. Another aspect of these studies, which we will address specifically, is the possibility that our receptor may provide insights for the development of more effective vaccines. Although much of our work will be performed using mouse models, we will also relate our findings to the human system, by showing that the human receptor functions in a similar manner in human cells. In addition, we will also examine the effect of various receptor polymorphisms; small genetic changes in the gene encoding the receptor which may have a significant effect on the receptors function. If we do find such influences, then ultimately we will explore the possibility of an association of these polymorphisms with alterations in disease susceptibility in human populations. We also have evidence that this receptor mediates its cellular functions through a novel mechanism. This mechanism involves transmitting information from the surface to the inside of the cell (intracellular signalling), and is critical for receptor function. Interestingly, we have evidence that our receptor does not transmit the intracellular signal directly, but rather associates with another molecule (an adaptor), which mediates this function. We wish to identify this adaptor molecule, which we will achieve using several different approaches, each of which involves established methodology. Once the adaptor is identified, then subsequent analysis will involve understanding its role in the receptor's function and in host immunity during mycobacterial infections. In sum, we have identified a novel receptor involved in anti-mycobacterial immunity, and the experiments described here will provide substantial and definitive insights into the role and functions of this receptor in both mice and humans.