Evidence indicates that individuals suffering from acquired immune deficiency syndrome (AIDS) are susceptible to severe systemic infections with mycobacteria in the Mycobacterium avium complex (MAC). Very little is known regarding the pathogenesis of the MAC but it has been proposed that these organisms are able to survive postphagocytic destruction because of an inert protective capsule, more recently referred to as the L1 layer. The long-term objective of this project is to study the pathogenic aspects of nontuberculous mycobacteria in the MAC using as a focal point a group of glycopeptidolipid (GPL) antigens which are the major constituent of the L1 layer and are the basis for serotyping mycbacteria in the MAC. Our previous studies have involved the GPL antigens of serovar 20, a MAC serovar not isolated from AIDS patients. The main objective of this proposal is to expand those studies by using the GPL antigens from serovars 4 and 8, the most common MAC serovars isolated from AIDS patients. This project is designed to examine with more specificity the postphagocytic handling of the GPL antigens by host macrophages to determine how they are processed by those cells and to what extent the antigens are degraded. GPL antigens will be labeled with radioisotopes by means of internal labeling techniques designed to radiolabel both the serovar-common fatty acyl peptide core and the serovar-specific oligosaccharide determinant. Radiolabeling will be accomplished with both (3H)- and (14C)-labeled components using techniques previously developed in this laboratory. Purified radiolabeled GPL antigens will be used to pulse both normal and """"""""activated"""""""" peritoneal macrophages which will subsequently be examined for potential GPL-catabolites. Postphagocytic distribution of the GPL antigens will be visually examined by means of immunocytochemical techniques using light and electron microscopy. Because there is a potential for GPL accumulation in host macrophages during an infection, the effect of GPL antigens on various macrophage functions will also be studied. These studies will make it possible to confirm whether these superfical antigens are inert to macrophage degradation and whether or not these antigens compromise the functional activity of host macrophages.
Specific aims are: 1) To confirm cell localization and distribution of GPL antigens from serovars 4 and 8, 2) To internally radiolabel the GPL antigens from serovars 4 and 8, 3) To examine the uptake and retention of GPL antigens by peritioneal macrophages, and 4) To examine the effect of GPL antigens on macrophage function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI021946-07
Application #
3132467
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1984-09-30
Project End
1993-03-31
Budget Start
1991-04-01
Budget End
1993-03-31
Support Year
7
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of North Texas
Department
Type
Schools of Osteopathy
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Horgen, L; Barrow, E L; Barrow, W W et al. (2000) Exposure of human peripheral blood mononuclear cells to total lipids and serovar-specific glycopeptidolipids from Mycobacterium avium serovars 4 and 8 results in inhibition of TH1-type responses. Microb Pathog 29:16-Sep
Rastogi, N; Goh, K S; Horgen, L et al. (1998) Synergistic activities of antituberculous drugs with cerulenin and trans-cinnamic acid against Mycobacterium tuberculosis. FEMS Immunol Med Microbiol 21:149-57
Barrow, W W (1997) Processing of mycobacterial lipids and effects on host responsiveness. Front Biosci 2:d387-400
Rastogi, N; Goh, K S; Van Ginkel, S Z et al. (1996) Identification of new drug targets in Mycobacterium avium and Mycobacterium tuberculosis. Res Microbiol 147:97-105
Wright, E L; Quenelle, D C; Suling, W J et al. (1996) Use of Mono Mac 6 human monocytic cell line and J774 murine macrophage cell line in parallel antimycobacterial drug studies. Antimicrob Agents Chemother 40:2206-8
Riviere, M; Puzo, G; Wright, E L et al. (1996) A unique phenylalanine-containing lipopeptide isolated from a rough-colony variant of Mycobacterium avium. Eur J Biochem 241:682-90
Wright, E L; Zywno-van Ginkel, S; Rastogi, N et al. (1996) Monoclonal infection involving Mycobacterium avium presenting with three distinct colony morphotypes. J Clin Microbiol 34:2475-8
Barrow, W W; Davis, T L; Wright, E L et al. (1995) Immunomodulatory spectrum of lipids associated with Mycobacterium avium serovar 8. Infect Immun 63:126-33
Rastogi, N; Goh, K S; Wright, E L et al. (1994) Potential drug targets for Mycobacterium avium defined by radiometric drug-inhibitor combination techniques. Antimicrob Agents Chemother 38:2287-95
Barrow, W W; de Sousa, J P; Davis, T L et al. (1993) Immunomodulation of human peripheral blood mononuclear cell functions by defined lipid fractions of Mycobacterium avium. Infect Immun 61:5286-93

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