Tuberculosis is endemic among patients with AIDS and follows an aggressive course with poorlocalization of mycobacteria into granuloma and widespread infection. Granulomas are monocyte richcollections of cells which derive from the circulating peripheral blood monocyte (PBMC). A classical responseagainst pathogens is the expression of cytoprotective genes including Heme-oxygenase-1 (HO-1) whichallows for a regulated inflammatory response as well as inhibits apoptosis of cells. Monocytes are recruited tothe site of tuberculous infection by the interaction of C-C chemokines, (mainly monocyte chemoattractantprotein-1, MCP- 1) and monocyte expression of the CCR2 receptor. It is the hypothesis of this proposal thatHO-1 expression in recruited monocyte-macrophages represents a critical regulatory event involved ineffective anti-mycobacterial host defense in tuberculosis. HO-1 depletion alters monocyte CCR2 expressionand thus recruitment and retention in granuloma as well as causing alterations in the signaling pathway leadingto their apoptosis and subsequent poor granuloma formation. We have developed a model of pleural tuberculosis in HO-1 -/- and HO-1 +/+ mice to evaluate the HO-1 mediated regulation of the CR2 receptor on PBMC and pleural macrophages (PM). We will evaluate ourhypothesis in our model of pleural tuberculosis in vivo as well as in vitro in PBMC and elicited pleuralmacrophages.
Our specific aims are:
Specific aim #1 : To evaluate the role of HO-1 in granuloma formation andmycobacterial clearance in a murine model of tuberculous pleurisy.
Specific aim #2 : To evaluate the regulatoryrole of HO-1 in the expression of CCR2 on peripheral blood monocytes and pleural macrophages duringgranuloma formation in the pleural space in tuberculous pleurisy.
Specific aim #3 : To evaluate the regulatoryrole of HO-1 in apoptosis of peripheral blood monocytes and pleural macrophages during granuloma formationin the pleural space in tuberculous pleurisy. Understanding the mechanisms underlying HO-1 mediated regulation of macrophage recruitment,retention and apoptosis, leading to granuloma formation is critical to the pathophysiology of pleuro-pulmonarytuberculosis seen in patients and will help develop therapeutic modalities that augment host-defenseresponses.
Project Summary: Understanding the mechanisms underlying HO-1 mediated regulation of macrophage recruitment, retention and apoptosis, leading to granuloma formation is critical to the pathophysiology of pleuro-pulmonary tuberculosis seen in patients and will help develop therapeutic modalities that augment host-defense responses.
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