The mycobacterium is a facultative intracellular pathogen of macrophages and dendritic cells and has proven to be the most difficult microbe for human macrophages/monocytes to kill. The mycobacterium accounts for several infectious diseases of great impact on human health noticeably including tuberculosis (TB) and M. avium infection. Incomplete understanding of the mechanisms of protective immune responses to mycobacterial infection has hindered the development of effective vaccines. It is generally believed that type 1 immunity characterized by T cell type 1 cytokine responses and macrophage granuloma formation is essential to host defense against mycobacterial infection. While a number of molecules, both soluble cytokines and cell surface molecules, have been found involved in the initiation and regulation of T cell and macrophage activation during mycobacterial infection, the role of other molecules has remained to be understood. Among these molecules is the recently identified transmembrane protein DAP12. DAP12 is primarily present on acrophages/monocytes, dendritic cells and NK cells and it serves as a signaling molecule for a group of cell surface immunoreceptor associated with DAP12, including TREM-1, TREM-2 and MDL-I. Recently emerging evidence from us and others has suggested that DAP-12-mediated signaling plays an important regulatory role in macrophage activation and inflammatory/immune responses. However, while its role in the development of type I immunity against intracellular bacterial pathogens including mycobacteria has remained completely unknown, our preliminary evidence has strongly implicated DAP12-mediated signaling pathway in host immune responses to mycobacterial infection. Thus, our current R03 proposal sets out to investigate a well-defined, novel question: whether and how DAP12 and its associating molecules are involved in the regulation of type 1 anti-mycobacterial immunity. This proposal carries the following specific AIMS: 1). Investigating the cellular source and regulation of expression of DAP12 and its associating molecules during mycobacterial infection; 2). Investigating the role of DAP12-mediated signaling in type 1 immune responses during mycobacterial infection. We strongly believe that our studies will provide new insights into the mechanisms of type 1 anti-microbial immunity and novel targets for immune modulation.
