The overall aim of this competing renewal project is to understand more fully the parasite:host cell interface and, thereby, define key elements that could be used for targets to control toxoplasmosis in AIDS patients. Work in the last funding period has allowed the demonstration that a specific parasite ligand:host cell receptor interaction occurs prior to the process of invasion. The work proposed here is for the identification of this host cell receptor that is unregulated during the S phase of the cell cycle. This gene will be isolated from a cDNA library and compared to other known eukaryotic receptor proteins. The receptor gene will be expressed in insect cells, nonpermissive for T. gondii infection, and the interaction between parasite and receptor studied. In addition, the receptor will be overexpressed or removed from other eukaryotic cells. SAG1 will be expressed in N. caninum to examine the specificity of the host cell receptor for SAG1.
The second aim i s to explore whether other parasite attachment ligands, in particular the MIC proteins, are important in the process of attachment and activation of human monocytes. Recent observations suggest MIC1 is involved in the interface between parasite attachment and invasion of human monocytes. Studies are proposed to determine whether MIC1 (and perhaps MIC2 and 3) are involved in this process by functional analysis of the MIC protein during the process of invasion and internalization in human monocytic cells. The innate immune response of monocytes stimulated by MIC engagement of the host cell receptor will be evaluated by determining the activation of two signal transduction pathways, induction of cytokines, and the production of a known soluble factor that downregulates host lymphoid proliferation. Strategies directed at interfering with attachment between parasite ligands and host cell receptor(s) should provide novel targets for the development of new therapeutic agents for treating this opportunistic infection in those afflicted with AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI030000-09
Application #
2544475
Study Section
Special Emphasis Panel (ZRG5-ARRB (02))
Project Start
1990-04-01
Project End
2003-05-31
Budget Start
1998-06-01
Budget End
1999-05-31
Support Year
9
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Courret, Nathalie; Darche, Sylvie; Sonigo, Pierre et al. (2006) CD11c- and CD11b-expressing mouse leukocytes transport single Toxoplasma gondii tachyzoites to the brain. Blood 107:309-16
Minns, Laurie A; Buzoni-Gatel, Dominique; Ely, Kenneth H et al. (2004) A novel triterpenoid induces transforming growth factor beta production by intraepithelial lymphocytes to prevent ileitis. Gastroenterology 127:119-26
Rachinel, Nicolas; Buzoni-Gatel, Dominique; Dutta, Chaitali et al. (2004) The induction of acute ileitis by a single microbial antigen of Toxoplasma gondii. J Immunol 173:2725-35
Kasper, Lloyd; Courret, Nathalie; Darche, Sylvie et al. (2004) Toxoplasma gondii and mucosal immunity. Int J Parasitol 34:401-9
Lee, Y H; Kasper, L H (2004) Immune responses of different mouse strains after challenge with equivalent lethal doses of Toxoplasma gondii. Parasite 11:89-97
Li, Wen; Buzoni-Gatel, Dominique; Debbabi, Hajer et al. (2002) CD40/CD154 ligation is required for the development of acute ileitis following oral infection with an intracellular pathogen in mice. Gastroenterology 122:762-73
Channon, Jacqueline Y; Miselis, Kristin A; Minns, Laurie A et al. (2002) Toxoplasma gondii induces granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor secretion by human fibroblasts: implications for neutrophil apoptosis. Infect Immun 70:6048-57
Kasper, L H; Buzoni-Gatel, D (2001) Ups and downs of mucosal cellular immunity against protozoan parasites. Infect Immun 69:1-8
Stommel, E W; Cho, E; Steide, J A et al. (2001) Identification and role of thiols in Toxoplasma gondii egress. Exp Biol Med (Maywood) 226:229-36
Channon, J Y; Seguin, R M; Kasper, L H (2000) Differential infectivity and division of Toxoplasma gondii in human peripheral blood leukocytes. Infect Immun 68:4822-6

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