Mycobacterium tuberculosis (MTB) organisms are known to attach to alveolar macrophages, to undergo phagocytosis and to survive and to replicate within the intracellular environment of the macrophage. The establishment of infection or the destruction of the invading microorganisms is likely determined within the first few days of the initial exposure; and yet, this initial response of the host (prior to the development of a specific immune response) is not well understood. The focus of this proposal is to understand the mechanisms of MTB interaction with alveolar macrophages. Hypothesis to be tested in this proposal is MTB organisms use surfactant apoproteins and/or adhesive proteins to promote the recruitment of attachment to, and phagocytosis by alveolar macrophages in a manner which permits continued survival of the microorganism. This hypothesis will be studied by investigating 5 Specific Aims: 1) To determine the mechanisms of alveolar macrophage chemotaxis to MTB organisms; 2) To determine mechanisms of MTB adherence to alveolar macrophages via adhesive proteins such as fibronectin or vitronectin; 3) To determine the mechanism of MTB adherence to surfactant (and subsequently alveolar macrophages) via surfactant apoproteins such as SP-A or SP-D; 4) To determine which mechanisms of MTB adherence (or phagocytosis) trigger the macrophage cytotoxic response O2-derived radical response or reactive nitrogen intermediate generation) and which do not; 5) To determine how human bronchoalveolar lavage fluids from normal and HIV-infected individuals influence macrophage chemotaxis, MTB adherence, phagocytosis and the triggering of the macrophage cytotoxic response. If successful, these studies should result in new and important information regarding the pathogenesis of pulmonary tuberculosis, and possibly, the risk of tuberculosis in HIV-infected individuals.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL051962-02
Application #
2229020
Study Section
Special Emphasis Panel (ZHL1-CSR-N (S3))
Project Start
1993-09-30
Project End
1998-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Davis, Ian C; Zhu, Sha; Sampson, Jacinda B et al. (2002) Inhibition of human surfactant protein A function by oxidation intermediates of nitrite. Free Radic Biol Med 33:1703-13
Pasula, Rajamouli; Wisniowski, Paul; Martin 2nd, William J (2002) Fibronectin facilitates Mycobacterium tuberculosis attachment to murine alveolar macrophages. Infect Immun 70:1287-92
Wisniowski, P E; Spech, R W; Wu, M et al. (2000) Vitronectin protects alveolar macrophages from silica toxicity. Am J Respir Crit Care Med 162:733-9
Perry, D G; Daugherty, G L; Martin 2nd, W J (1999) Clathrin-coated pit-associated proteins are required for alveolar macrophage phagocytosis. J Immunol 162:380-6
Downing, J F; Kachel, D L; Pasula, R et al. (1999) Gamma interferon stimulates rat alveolar macrophages to kill Pneumocystis carinii by L-arginine- and tumor necrosis factor-dependent mechanisms. Infect Immun 67:1347-52
Pasula, R; Wright, J R; Kachel, D L et al. (1999) Surfactant protein A suppresses reactive nitrogen intermediates by alveolar macrophages in response to Mycobacterium tuberculosis. J Clin Invest 103:483-90
Pasula, R; Downing, J F; Wright, J R et al. (1997) Surfactant protein A (SP-A) mediates attachment of Mycobacterium tuberculosis to murine alveolar macrophages. Am J Respir Cell Mol Biol 17:209-17
Perry, D G; Wisniowski, P; Daugherty, G L et al. (1997) Nonimmune phagocytosis of liposomes by rat alveolar macrophages is enhanced by vitronectin and is vitronectin-receptor mediated. Am J Respir Cell Mol Biol 17:462-70
Weaver, T; Hall, C L; Kachel, D L et al. (1996) Assessment of in vivo attachment/phagocytosis by alveolar macrophages. J Immunol Methods 193:149-56
Williams, M D; Wright, J R; March, K L et al. (1996) Human surfactant protein A enhances attachment of Pneumocystis carinii to rat alveolar macrophages. Am J Respir Cell Mol Biol 14:232-8

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