Tuberculosis is the leading cause of death due to an infectious disease in the world. As a pulmonary pathogen, the initial interaction between the causative bacterium Mycobacterium tuberculosis (M.tb) and the human host is in the lung where surfactant, epithelial cells, and alveolar macrophages are located. This initial interaction between these components of the alveolus and M.tb dictate the outcome of infection. The understanding of this process is limited, but critical in this disease. This five year award will provide insight into the pathogenesis of tuberculosis, specifically in the role that surfactant components play in the early host response to this host-adapted microorganism.
The specific aims are to: characterize the binding of surfactant protein D (SP-D) to virulent and attenuated M.tb strains, and their major surface components, and to determine the impact of this binding on bacterial agglutination; determine if SP-D alone or in conjunction with surfactant protein A (SP-A), and the major surfactant phospholipid, dipalmitoyl phosphatidylcholine (DPPC), influences the phagocytosis of M.tb by macrophages; determine if SP-D, SP-A, and DPPC influence the intracellular survival of M.tb in the macrophage, and to examine whether this is the result of altered cellular responses such as phagosome-lysosome fusion or the oxidative burst; and, determine if SP-D, SP-A, and DPPC influence the M.tb-pulmonary epithelial cell interaction.
These specific aims will be accomplished using in vitro techniques available at the primary laboratory and through collaborative efforts. The candidate is a fellow in the Division of Pulmonary, Critical Care, and Occupational Medicine. Through an intense course of didactic and laboratory study, he will define the essential role that surfactant components play in the host defense response to M.tb using methods of microbiology, immunology, biochemistry, molecular biology, and cell physiology. He will determine the role that SP-A, SP-D, and DPPC, have in regulating the immune response of macrophages and epithelial cells to this intracellular pathogen. The proposed work will be performed at the University of Iowa, a well-known leader in biomedical research. The work to be performed encompasses the Division of Infectious Diseases and the Division of Pulmonary, Critical Care, and Occupational Medicine, as well as various departments from the College of Medicine. Laboratory facilities are at the Iowa City Veterans Administration Center, and the University of Iowa. The candidate, mentors, advisory committee, and collaborators will work closely to achieve the goals of this proposed award: to define critical interactions between the human pathogen M.tb and the host, and for the principal investigator to become an accomplished independent biomedical investigator.
|Ferguson, J Scott; Martin, Jennifer L; Azad, Abul K et al. (2006) Surfactant protein D increases fusion of Mycobacterium tuberculosis-containing phagosomes with lysosomes in human macrophages. Infect Immun 74:7005-9|
|Ferguson, J Scott; Weis, Jeremy J; Martin, Jennifer L et al. (2004) Complement protein C3 binding to Mycobacterium tuberculosis is initiated by the classical pathway in human bronchoalveolar lavage fluid. Infect Immun 72:2564-73|
|Crowther, Joy E; Kutala, Vijay Kumar; Kuppusamy, Periannan et al. (2004) Pulmonary surfactant protein a inhibits macrophage reactive oxygen intermediate production in response to stimuli by reducing NADPH oxidase activity. J Immunol 172:6866-74|
|Ferguson, J Scott; Voelker, Dennis R; Ufnar, Jennifer A et al. (2002) Surfactant protein D inhibition of human macrophage uptake of Mycobacterium tuberculosis is independent of bacterial agglutination. J Immunol 168:1309-14|
|Ferguson, J S; Schlesinger, L S (2000) Pulmonary surfactant in innate immunity and the pathogenesis of tuberculosis. Tuber Lung Dis 80:173-84|
|Mares, D C; Heidler, K M; Smith, G N et al. (2000) Type V collagen modulates alloantigen-induced pathology and immunology in the lung. Am J Respir Cell Mol Biol 23:62-70|
|Sekine, Y; Yasufuku, K; Heidler, K M et al. (2000) Monocyte chemoattractant protein-1 and RANTES are chemotactic for graft infiltrating lymphocytes during acute lung allograft rejection. Am J Respir Cell Mol Biol 23:719-26|
|Ferguson, J S; Voelker, D R; McCormack, F X et al. (1999) Surfactant protein D binds to Mycobacterium tuberculosis bacilli and lipoarabinomannan via carbohydrate-lectin interactions resulting in reduced phagocytosis of the bacteria by macrophages. J Immunol 163:312-21|
|Sekine, Y; Bowen, L K; Heidler, K M et al. (1997) Role of passenger leukocytes in allograft rejection: effect of depletion of donor alveolar macrophages on the local production of TNF-alpha, T helper 1/T helper 2 cytokines, IgG subclasses, and pathology in a rat model of lung transplantation. J Immunol 159:4084-93|
|Maruyama, T; Richardson, L C; Sun, W et al. (1995) Acute effects of amiodarone on membrane properties, refractoriness, and conduction in guinea pig papillary muscles. Heart Vessels 10:78-86|
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