Tuberculosis (TB) is the most common fatal infectious disease in the world, and remains a threat to health in the United States. While improved case finding and access to treatment have reduced the incidence of TB in the United States, further improvements in TB control and therapy depend on better understanding of the pathogenesis of TB. Macrophages are essential for defense against infections, and are central to the pathogenesis of TB. When macrophages encounter most bacteria, they phagocytose and kill them. In contrast, macrophages phagocytose, but do not kill M. tuberculosis, even when they are stimulated with IFN gamma. Recent experiments in the PI's laboratory reveal that one means that M. tuberculosis uses to evade killing by macrophages is to block the signal transduction pathway initiated by interferon gamma. The PI has found that infection of macrophages with M. tuberculosis blocks several macrophage responses to IFN gamma, and has found that this disruption of signalling reduces transcriptional activation of IFN gamma-responsive genes at a distal step in the signalling pathway. M. tuberculosis infection of macrophages causes release of one or more soluble factors that inhibit IFN gamma signaling in uninfected macrophages. TGF-beta, IL-4, IL-6, IL-10, and prostaglandin E2 cannot account for this phenomenon. The PI proposes to identify the component of M. tuberculosis that initiates the inhibition of IFN gamma signaling. One hypothesis to be tested is that infection of macrophages by M. tuberculosis induces a repressor that binds specific DNA elements in the promoter region of interferon gamma-responsive genes. Finally, the PI will purify the soluble factor present in the conditioned medium from infected cells that inhibits interferon gamma signaling in uninfected macrophages. The proposed experiments will enhance the understanding of the pathogenesis of tuberculosis, and will provide insight essential for developing effective approaches to enhancing the protective immune response to M. tuberculosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL051992-06
Application #
6389348
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Peavy, Hannah H
Project Start
1993-09-30
Project End
2003-08-31
Budget Start
2001-09-01
Budget End
2003-08-31
Support Year
6
Fiscal Year
2001
Total Cost
$242,369
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Nagabhushanam, Vijaya; Solache, Alejandra; Ting, Li-Min et al. (2003) Innate inhibition of adaptive immunity: Mycobacterium tuberculosis-induced IL-6 inhibits macrophage responses to IFN-gamma. J Immunol 171:4750-7
Peters, W; Scott, H M; Chambers, H F et al. (2001) Chemokine receptor 2 serves an early and essential role in resistance to Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 98:7958-63
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Ernst, J D (2000) Bacterial inhibition of phagocytosis. Cell Microbiol 2:379-86
Ting, L M; Kim, A C; Cattamanchi, A et al. (1999) Mycobacterium tuberculosis inhibits IFN-gamma transcriptional responses without inhibiting activation of STAT1. J Immunol 163:3898-906
Majeed, M; Perskvist, N; Ernst, J D et al. (1998) Roles of calcium and annexins in phagocytosis and elimination of an attenuated strain of Mycobacterium tuberculosis in human neutrophils. Microb Pathog 24:309-20
Ernst, J D (1998) Macrophage receptors for Mycobacterium tuberculosis. Infect Immun 66:1277-81
Larsson, M; Majeed, M; Ernst, J D et al. (1997) Role of annexins in endocytosis of antigens in immature human dendritic cells. Immunology 92:501-11

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