The immune response to Mycobacterium tuberculosis (M. tuberculosis) is determined by antigen independent as well as by Ag-specific interactions. We propose that adhesive molecules required for the Ag independent response regulate the development of the host response to M. tuberculosis. We propose to characterize the expression of the immunoglobulin gene superfamily of adhesive molecules, intercellular adhesion molecules-1,2,3 (ICAM) and vascular cell adhesion molecule-1 (VCAM) in response to M. tuberculosis. We will determine whether increased expression of surface adhesion molecules (ICAM-1,2,3,VCAM-1) is critical for accessory cell function of mononuclear phagocytes in response to M.tuberculosis. We will evaluate th in vivo expression of ICAM-1,2,3 and VCAM-1 in response to M.tuberculosis infection in resting and stimulated alveolar macrophages (Ams) derived from normal subjects and those infected with M.tuberculosis (immunohistochemistry, fluorescent flow cytometry). We will correlate these studies with the in vivo expression of ICAM/VAM in tuberculous granulomas derived from biopsy specimens of the lung or pleura (Immunofluorescence, immunoelectron microscopy) and the release of soluble ICAM 1 in bronchoalveolar lavage fluid. We will extend these studies to evaluate the regulation of expression of ICAM, VCAM and sICAM will be characterized in monocytic cells (THP-1 cells, peripheral blood monocytes, Ams) in response to M.tuberculosis and its cell wall components (liparabinomannan, deacylated LAM, H37Ra and Erdman strains) at the protein level (fluorescence flow cytometry, immunohistochemistry, immunoprecipitation) and molecular level (PCR, northern analysis). We will begin to decipher the mechanisms by which M.tuberculosis and its cell wall components elicit cell responses by evaluation of the generation of early intracellular signals. We will evaluate the kinetics of production of intracellular signals derived from phospholipid metabolism.(diacylglycerol, alkyl-acyl glycerol, phosphatidate, phosphatidylinositol 4,5 bis phosphate, inositol 1,45 trisphosphate). We will determine whether cell responses to M.tuberculosis are mediated by the rapid activation of protein kinases (PKC(s), CAMP-d kinases, tyrosine kinase, MAP kinase ) or by the activation of serine/threonine- specific protein phosphatases.
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