Pneumocystis carinii (PC), an obligate extracellular pathogen, is a major cause of opportunistic infection in the lung. PC pneumonia develops in up to 80% of patients with acquired immune deficiency syndrome (AIDS) and is the major identifiable cause of death in 1/3 of patients with AIDS. Three key features of PC pneumonia include: 1) PC is an extracellular pathogen which selectively binds to Type I alveolar epithelial cells, 2) PC organisms are intimately associated with surfactant during attachment to the alveolar epithelium and 3) as PC pneumonia develops, PC eventually detach from the alveolar epithelial surface and epithelial cell injury becomes evident. However, mechanisms underlying the interaction of PC with alveolar epithelial cells are poorly understood. To address possible mechanisms, we have hypothesized: gp120 on the surface of PC mediates attachment to alveolar epithelial cells by a fibronectin- and/or surfactant protein A-dependent mechanism which ultimately results in protease-mediated detachment of PC from the epithelial cell. Using an in vitro model system developed in our laboratory, we propose to examine the following Specific Aims: 1) to determine if gp120 is a fibronectin (Fn)-binding glycoprotein with structural homology to known integrins, 2) to determine if gp120 binding to Fn mediates attachment to alveolar epithelial cells, 3) to determine if gp120 binds surfactant protein A (SPA) by a mannose-dependent mechanism, 4) to determine if PC binding to SPA mediates attachment to alveolar epithelial cells, 5) to determine if PC possess proteases capable of mediating detachment from alveolar epithelial cells. We speculate that PC-derived proteases may inadvertently damage target epithelial cells and possibly facilitate detachment of the epithelial cell from the basal lamina. We believe that our approach to examining PC infection is fundamentally different from prior work in the field and should result in the development of new and important information regarding specific mechanisms operative in PC pneumonia. If successful, these studies may potentially suggest novel therapeutic strategies for this devastating opportunistic lung infection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL046647-01
Application #
3365750
Study Section
Special Emphasis Panel (SRC (JJ))
Project Start
1991-08-19
Project End
1994-07-31
Budget Start
1991-08-19
Budget End
1992-07-31
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Pasula, Rajamouli; Wisniowski, Paul; Martin 2nd, William J (2002) Fibronectin facilitates Mycobacterium tuberculosis attachment to murine alveolar macrophages. Infect Immun 70:1287-92
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
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
Boelaert, J R; Weinberg, G A; Weinberg, E D (1996) Altered iron metabolism in HIV infection: mechanisms, possible consequences, and proposals for management. Infect Agents Dis 5:36-46
Su, T H; Natarajan, V; Kachel, D L et al. (1996) Functional impairment of bronchoalveolar lavage phospholipids in early Pneumocystis carinii pneumonia in rats. J Lab Clin Med 127:263-71
Martin 2nd, W J; Downing, J F; Williams, M D et al. (1995) Role of surfactant protein A in the pathogenesis of tuberculosis in subjects with human immunodeficiency virus infection. Proc Assoc Am Physicians 107:340-5
McMahon, J P; Wheat, J; Sobel, M E et al. (1995) Murine laminin binds to Histoplasma capsulatum. A possible mechanism of dissemination. J Clin Invest 96:1010-7
Downing, J F; Pasula, R; Wright, J R et al. (1995) Surfactant protein a promotes attachment of Mycobacterium tuberculosis to alveolar macrophages during infection with human immunodeficiency virus. Proc Natl Acad Sci U S A 92:4848-52
Weinberg, G A; Edlind, T D; Lu, J J et al. (1994) Genetic diversity of Pneumocystis carinii from different host species at the beta-tubulin gene locus and at the internal transcribed spacer regions of the rRNA gene cluster. J Eukaryot Microbiol 41:118S

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