The long term goals of this continuing R-01 proposal are to further understand the immunology of the opportunistic pathogen, Toxoplasma gondii. Although the development of a protective vaccine would be the ideal achievement, the complex antigenic character of the eucaryote first must be understood. Earlier studies have dealt with the identification and isolation of those toxoplasma antigens that induce host immunity. These studies have resulted in the development of a scheme for elucidating the humoral and cellular response to this obligate intracellular parasite that is a significant cause of morbidity in neonates and those afflicted with AIDS. Over the next five years, further investigation into the antigenic character of T. gondii is proposed. The first specific aim will be to evaluate the cellular immune response to various T. gondii antigens including the major surface protein, P30. By T cell clonal analysis those antigens that induce a lymphoproliferative response will be identified. Those T cell exhibiting cytotoxicity against T. gondii will be evaluated. We will determine if the cytotoxic T cells are MHC restricted. The functional helper T cell response induced by these parasite antigens during infection of resistant and susceptible inbred mouse strains will be studied. The paradoxical immune response observed in mice to P30 will be further investigated by developing a panel of mouse and human P30 antigen specific T cell clones. The critical immune epitopes necessary for stimulation of the protective T cells will be identified, characterized and synthesized in vitro. The parasite antigen that induces the RTg1 cloned human cytotoxic T cell line will be isolated and characterized by immunochemical and molecular approaches.The second specific aim is to further evaluate a panel of antibody resistant mutants that exhibit decreased virulence in vivo. These mutants will be phenotyped in vivo and their ability to induce proliferation of T cell clones assessed. Virulence factors associated with the antibody resistant mutants will be assessed by in vitro transformation studies. These antigen deficient mutants will be used to investigate antigen presentation in an MHC restricted system. All of these specific aims will define strategies to augment the host immune response to this opportunistic infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Tropical Medicine and Parasitology Study Section (TMP)
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Dartmouth College
Internal Medicine/Medicine
Schools of Medicine
United States
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Foureau, David M; Mielcarz, Daniel W; Menard, Laurence C et al. (2010) TLR9-dependent induction of intestinal alpha-defensins by Toxoplasma gondii. J Immunol 184:7022-9
Begum-Haque, Sakhina; Haque, Azizul; Kasper, Lloyd H (2009) Apoptosis in Toxoplasma gondii activated T cells: the role of IFNgamma in enhanced alteration of Bcl-2 expression and mitochondrial membrane potential. Microb Pathog 47:281-8
Lu, Fangli; Huang, Shiguang; Kasper, Lloyd H (2009) The temperature-sensitive mutants of Toxoplasma gondii and ocular toxoplasmosis. Vaccine 27:573-80