Mycobacteria are major causes of opportunistic infection in the acquired immunodeficiency syndrome (AIDS). By 1991, approximately 146,000 AIDS patients in the United States will have developed infections with Mycobacterium avium or Mycobacterium tuberculosis. More completer understanding of the pathogenesis and pathophysiology of mycobacterial infection is essential to devise new strategies for prevention and treatment since existing modalities often are inadequate. The proposal tests two interconnected hypotheses: a) the systemic effects of intracellular parasitism by M. avium are mitigated by blockade in IL-1/TNF production; but there is concurrent compromise of effector and accessory function of mononuclear phagocytes; and b) infection with human immunodeficiency virus (HIV) is associated with a primary defect in killing of M. tuberculosis and M. avium by mononuclear phagocytes, possibly compounded by suboptimal responses to macrophage activating factors.
Specific aims to test these hypotheses are: 1) To identify activating factors which promote growth inhibition or killing of M. avium, M. tuberculosis, Toxoplasma gondii and tumors by mononuclear phagocytes from healthy donors and to examine the association of intracellular growth with serovar, plasmid content, mouse virulence, and source of M. avium isolates; 2) To determine whether M. avium and M. tuberculosis infection of mononuclear phagocytes from healthy subjects interferes with cellular secretory, immunoregulatory and effector functions; and 3) To examine mycobacterial phagocytosis and growth inhibition by mononuclear phagocytes and augmentation of effector functions by macrophage activating factors (MAF) subjects with HIV infection. This research is health-related.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI025799-02
Application #
3139423
Study Section
(SRC)
Project Start
1987-09-30
Project End
1992-08-31
Budget Start
1988-09-01
Budget End
1989-08-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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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