M. tuberculosis (MTB) infects nearly one third of the world's population and causes significant mortality. MTB is in an intracellular pathogen of mononuclear phagocytes (MP) that is highly adapted to the human host. Research to define the molecular events underlying the MTB-MP interaction is necessary to enhance our understanding of disease pathogenesis. Entry of MTB into human MP's occurs by receptor-members of the B2 (leukocyte) integrin family, proteins which mediate cellular adhesion. Preliminary experiments to map the binding sites suggest that MTB binds primarily to the I domain of CR3 rather than activation of lectin sites. Thus, the investigators hypothesize that early survival of M.tb during phagocytosis may relate to its binding to a non-activating epitope on the receptor. The macrophage mannose receptor, in addition to CR's, participates in the phagocytosis of virulent M.tb. The investigators have developed new transfected human myeloid cell lines containing each of the major receptors for M.tb phagocytes and thus will test the hypothesis that the receptors ligated during entry impact on the fate of the pathogen. Finally, their preliminary data indicate that during intracellular growth of M.tb in macrophages, there is a marked alteration in the biosynthesis, surface expression and function of B2 integrins. Thus, they hypothesize that the M.tb-infected macrophage represents an altered cell type with decreased phagocytic capabilities and enhanced adhesive functions.
The AIMS are to: 1) characterize the molecular determinants for CR-dependent M.tb phagocytosis; 2) characterize the influence of M.tb growth in macrophages on the biosynthesis and surface expression of B2 integrins; and 3) characterize the influence of M.tb intracellular growth on the function of B2 integrins. The methods to accomplish these tasks will include cell culture, biochemical and molecular techniques. This proposal will provide insight into intracellular pathogenesis and B2 integrin biology, an area that relates to vascular biology, inflammation, and cellular communication. Their goal is to better characterize the molecular interactions that occur during the early M.tb-MP interaction in order to enhance our understanding of disease pathogenesis. Ultimately these studies may help to define specific novel therapeutic targets.
| Yang, Lanhao; Sinha, Tejas; Carlson, Tracy K et al. (2013) Changes in the major cell envelope components of Mycobacterium tuberculosis during in vitro growth. Glycobiology 23:926-34 |
| Torrelles, Jordi B; Sieling, Peter A; Arcos, Jesús et al. (2011) Structural differences in lipomannans from pathogenic and nonpathogenic mycobacteria that impact CD1b-restricted T cell responses. J Biol Chem 286:35438-46 |
| Torrelles, Jordi B; Schlesinger, Larry S (2010) Diversity in Mycobacterium tuberculosis mannosylated cell wall determinants impacts adaptation to the host. Tuberculosis (Edinb) 90:84-93 |
| Torrelles, Jordi B; DesJardin, Lucy E; MacNeil, Jessica et al. (2009) Inactivation of Mycobacterium tuberculosis mannosyltransferase pimB reduces the cell wall lipoarabinomannan and lipomannan content and increases the rate of bacterial-induced human macrophage cell death. Glycobiology 19:743-55 |
