Mycobacterium avium is the most frequent cause of disseminated bacterial infection in patients infected with human immunodeficiency virus (HIV) and is associated with morbidity and shortened survival. It is not clear why M. avium infection is more common in HIV-infected persons than in other groups of immunocompromised individuals and reaches such high levels in tissues (10 9- 10/g). The regulation of the growth of M. avium within mononuclear phagoytes and the infected host is the subject of AI25799. Colonial morphotype is a reliable determinant of the potential for intracellular replication. Smooth, flat-transparent (SmT) isolates are phagocytosed less well, but undergo more intracellular replication than smooth domed-opaque (SmD) colonies, and differ in their capacity to induce expression of interleukin-1, and tumor necrosis factor, but not IL-6. Cytokines have bidirectional effects on the intracellular growth of M. avium; and IL-1 alpha and IL-6 also promote extracellular growth. Purified gp120 protein of HIV also appears to modulate phagocytosis and intracellular growth of M. avium, and multinucleated giant cell formation by monocytes. These observations suggest that differential induction of cytokines by M. avium colonial morphotypes, possibly as modulated by HIV- products, determines the growth characteristics of M. avium in the mononuclear phagocyte, and in the tissues of patients infected with HIV. Testing of this hypothesis and initial exploration of its potential relevance in the HIV-infected host will require in vivo and in vitro studies in healthy and HIV-infected persons. Accordingly, the Specific Aims to test this hypothesis are: (1) To explore whether the growth- enhancing properties of IL-1 and IL-6 for M. avium are associated with binding to receptors on the organisms, and account for intracellular growth characteristics; and whether these cytokines promote M. avium growth in the monocytes and tissues of HIV-infected persons. (2) To examine the potential role of glycopeptidolipids and lipoarabinomannans of M. avium in the differential induction of cytokines by SmT and SmD strains; and the effects of these organisms and their constituents on the intracellular pathways of cytokine expression within the mononuclear phagocyte. (3) To determine the basis for the interference by HIV gp120 with the phagocytosis and intracellular growth inhibition of M. avium by human monocytes and with multinucleated giant cell formation, in terms of modulation of cell surface receptors, cytokine expression, and effector function. These studies should provide novel insights into the pathogenesis of and potential therapeutic approaches to M. avium in HIV-infected subjects, and the means by which viral products and induction of host cytokines contribute to successful parasitism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI025799-16
Application #
6373128
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Program Officer
Near, Karen A
Project Start
1987-09-30
Project End
2004-05-31
Budget Start
2001-06-01
Budget End
2004-05-31
Support Year
16
Fiscal Year
2001
Total Cost
$282,018
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Newark
State
NJ
Country
United States
Zip Code
07107
Shiratsuchi, H; Ellner, J J (2001) Expression of IL-18 by Mycobacterium avium-infected human monocytes; association with M. avium virulence. Clin Exp Immunol 123:203-9
Shiratsuchi, H; Krukovets, I; Ellner, J J (2000) Role of T cell subsets in the modulation of Mycobacterium avium growth within human monocytes. Cell Immunol 202:12-Jun
Johnson, J L; Shiratsuchi, H; Toossi, Z et al. (1997) Altered IL-1 expression and compartmentalization in monocytes from patients with AIDS stimulated with Mycobacterium avium complex. J Clin Immunol 17:387-95
Shiratsuchi, H; Hamilton, B; Toossi, Z et al. (1996) Evidence against a role for interleukin-10 in the regulation of growth of Mycobacterium avium in human monocytes. J Infect Dis 173:410-7
Hirsch, C S; Ellner, J J; Russell, D G et al. (1994) Complement receptor-mediated uptake and tumor necrosis factor-alpha-mediated growth inhibition of Mycobacterium tuberculosis by human alveolar macrophages. J Immunol 152:743-53
Shiratsuchi, H; Johnson, J L; Toossi, Z et al. (1994) Modulation of the effector function of human monocytes for Mycobacterium avium by human immunodeficiency virus-1 envelope glycoprotein gp120. J Clin Invest 93:885-91
Shiratsuchi, H; Toossi, Z; Mettler, M A et al. (1993) Colonial morphotype as a determinant of cytokine expression by human monocytes infected with Mycobacterium avium. J Immunol 150:2945-54
Mirando, W S; Shiratsuchi, H; Tubesing, K et al. (1992) Ultraviolet-irradiated monocytes efficiently inhibit the intracellular replication of Mycobacterium avium intracellulare. J Clin Invest 89:1282-7
Shiratsuchi, H; Johnson, J L; Ellner, J J (1991) Bidirectional effects of cytokines on the growth of Mycobacterium avium within human monocytes. J Immunol 146:3165-70
Johnson, J L; Shiratsuchi, H; Toba, H et al. (1991) Preservation of monocyte effector functions against Mycobacterium avium-M. intracellulare in patients with AIDS. Infect Immun 59:3639-45

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