The goal of the proposed studies is to determine the antibacterial functions of tumor necrosis factor (TNF), interleukin-1s (IL-1),l and the interferons (IFN). Models of acute or chronic murine listeriosis will be employed to analyze the functions of these cytokines in host defense against a facultative intracellular pathogen. Pure preparations of murine cytokines will be administered prophylactically, or therapeutically to Listeria-infected mice to determine whether they enhance nonspecific resistance mechanisms, and/or specific T cell-mediated anti-Listeria immunity. The temporal appearance and quantities of cytokines produced in organs in response to infection will be measured, and roles for these Listeria-induced molecules in resistance will be established by determining whether the administration of specific anti-cytokine neutralizing antibodies results in an exacerbation of infection. It is anticipated that resident tissue macrophages and recruited bone marrow-derived macrophages that mediated Listeria destruction are probably major sources of Listeria- induced TNF, IL-1, IFNalpha and IFNbeta. In vitro studies will examine the listericidal actions of Kupffer cells and recruited macrophages following treatment with each of these cytokines. Other studies will examine whether the cytokines in question can function to either induce macrophage monokine synthesis, or prime macrophages for enhanced monokine production in response to Listeria ingestion. Because it has now been definitely established that Listeria multiplies in hepatocytes in vivo, studies will be undertaken to determine whether the aforementioned cytokines can render hepatocytes resistant to penetration or intracellular multiplication of Listeria. It will also be determined whether TNF, Listeria-sensitized T cells, or natural killer cells are capable of lysing Listeria-infected hepatocytes or fibroblasts. Other studies will examine whether cytokines can enhance the cytolytic activity of TNF, or host effector cells for Listeria-infected nonprofessional phagocytic cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI023544-05
Application #
3135818
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1986-05-01
Project End
1994-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
5
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Trudeau Institute, Inc.
Department
Type
DUNS #
City
Saranac Lake
State
NY
Country
United States
Zip Code
12983
Havell, E A; Rogerson, B J (1993) Endotoxin-induced tumor necrosis factor alpha synthesis in murine embryo fibroblasts. Infect Immun 61:1630-5
Chen, W; Havell, E A; Gigliotti, F et al. (1993) Interleukin-6 production in a murine model of Pneumocystis carinii pneumonia: relation to resistance and inflammatory response. Infect Immun 61:97-102
Johnson, L L; VanderVegt, F P; Havell, E A (1993) Gamma interferon-dependent temporary resistance to acute Toxoplasma gondii infection independent of CD4+ or CD8+ lymphocytes. Infect Immun 61:5174-80
Havell, E A (1993) Listeria monocytogenes-induced interferon-gamma primes the host for production of tumor necrosis factor and interferon-alpha/beta. J Infect Dis 167:1364-71
Havell, E A; Moldawer, L L; Helfgott, D et al. (1992) Type I IL-1 receptor blockade exacerbates murine listeriosis. J Immunol 148:1486-92
Chen, W; Havell, E A; Moldawer, L L et al. (1992) Interleukin 1: an important mediator of host resistance against Pneumocystis carinii. J Exp Med 176:713-8
Chen, W; Havell, E A; Harmsen, A G (1992) Importance of endogenous tumor necrosis factor alpha and gamma interferon in host resistance against Pneumocystis carinii infection. Infect Immun 60:1279-84
Havell, E A (1992) Role of TNF in resistance to bacteria. Immunol Ser 56:341-63
Havell, E A; Sehgal, P B (1991) Tumor necrosis factor-independent IL-6 production during murine listeriosis. J Immunol 146:756-61
Vogel, S N; Havell, E A (1990) Differential inhibition of lipopolysaccharide-induced phenomena by anti-tumor necrosis factor alpha antibody. Infect Immun 58:2397-400

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