: Toxoplasmic encephalitis (TE) is a life-threatening disease in immunocompromised patients such as those with AIDS. The immunopathogenesis of TE remains to be defined. We have identified three factors to be critical for determining the host resistance to this disease. These are IFN-gamma-mediated immune response, the genetic background of the host and the strain (antigens) of T. gondii. It appears that the genetic background of the hostand the strain (antigens) of T. gondii affect the IFN-gamma-mediated immune response, thereby contribute to determining the host resistance. Thus, for obtaining understanding of the molecular basis of host resistance to TE, I propose to define the mechanisms how IFN-gamma-mediated immune response is operated in the brain and how the genetic background of the host and the strain (antigens) of T. gondii affect the immune response. To accomplish this long-term specific aim, I will address three main questions in this proposal. My recent preliminary studies demonstrated that infected athymic nude and SCID mice, which lack T cells, had high levels of IFN-gamma expression in their brains. Another series of preliminary studies using a transfer of immune T cells demonstrated that such IFN-gamma expression by the non-T cell(s) is required for transferred immune T cells to demonstrate their protective activity in the brain to prevent TE. Thus, the first specific aim is to identify the non-T cell(s) which produces IFN-gamma in the brain and to analyze the role and function of T cells in their collaboration with the non-T cell(s) for prevention of TE. The second specific aim is to analyze the mechanism of T cell entry into the brain in infected host. T cells need to enter the brain to exert their protective activity. My preliminary studies suggested an important role for IFN-gamma, in regulating T cell trafficking into the brain of infected mice. Thus, I propose to analyze the role for IFN-gamma, in regulation of expression of adhesion molecules involved in cell trafficking on cerebral vessels and T cells. Under this specific aim, I also propose to analyze the role of IFN-gamma and adhesion molecules on the T cell entry into the brain. The third specific aim to address the effects of host genes on the protective immune response to TE. Since my preliminary studies revealed an importance of Vbeta8-bearing T cells in genetic resistance of BALB/c mice to TE, I propose to analyze the mechanism of the protective activity of this T cell population in their resistance. I also propose to analyze T. gondii antigen(s) which stimulate Vbeta8-bearing T cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047730-03
Application #
6619471
Study Section
Special Emphasis Panel (ZRG1-AARR-4 (01))
Program Officer
Wali, Tonu M
Project Start
2001-09-24
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
3
Fiscal Year
2003
Total Cost
$292,400
Indirect Cost
Name
Virginia Polytechnic Institute and State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
003137015
City
Blacksburg
State
VA
Country
United States
Zip Code
24061
Wang, Xisheng; Suzuki, Yasuhiro (2007) Microglia produce IFN-gamma independently from T cells during acute toxoplasmosis in the brain. J Interferon Cytokine Res 27:599-605
Wang, Xisheng; Michie, Sara A; Xu, Baohui et al. (2007) Importance of IFN-gamma-mediated expression of endothelial VCAM-1 on recruitment of CD8+ T cells into the brain during chronic infection with Toxoplasma gondii. J Interferon Cytokine Res 27:329-38
Miller, Renee; Wen, Xiangshu; Dunford, Bradley et al. (2006) Cytokine production of CD8+ immune T cells but not of CD4+ T cells from Toxoplasma gondii-infected mice is polarized to a type 1 response following stimulation with tachyzoite-infected macrophages. J Interferon Cytokine Res 26:787-92
Rodgers, Laurel; Wang, Xisheng; Wen, Xiangshu et al. (2005) Strains of Toxoplasma gondii used for tachyzoite antigens to stimulate spleen cells of infected mice in vitro affect cytokine responses of the cells in the culture. Parasitol Res 97:332-5
Suzuki, Yasuhiro; Claflin, Jennifer; Wang, Xisheng et al. (2005) Microglia and macrophages as innate producers of interferon-gamma in the brain following infection with Toxoplasma gondii. Int J Parasitol 35:83-90
Wang, Xisheng; Claflin, Jennifer; Kang, Hoil et al. (2005) Importance of CD8(+)Vbeta8(+) T cells in IFN-gamma-mediated prevention of toxoplasmic encephalitis in genetically resistant BALB/c mice. J Interferon Cytokine Res 25:338-44
Last, Robert D; Suzuki, Yasuhiro; Manning, Thomas et al. (2004) A case of fatal systemic toxoplasmosis in a cat being treated with cyclosporin A for feline atopy. Vet Dermatol 15:194-8
Wang, Xisheng; Kang, Hoil; Kikuchi, Takane et al. (2004) Gamma interferon production, but not perforin-mediated cytolytic activity, of T cells is required for prevention of toxoplasmic encephalitis in BALB/c mice genetically resistant to the disease. Infect Immun 72:4432-8
Grigg, Michael E; Suzuki, Yasuhiro (2003) Sexual recombination and clonal evolution of virulence in Toxoplasma. Microbes Infect 5:685-90
Kang, Hoil; Liesenfeld, Oliver; Remington, Jack S et al. (2003) TCR V beta 8+ T cells prevent development of toxoplasmic encephalitis in BALB/c mice genetically resistant to the disease. J Immunol 170:4254-9

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