IMMUNE REGULATION IN TOXOPLASMOSIS AND OTHER OPPORTUNISTIC INFECTIONS

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The overall aim of this project is to analyze the immune response to Toxoplasma gondii and other intracellular opportunistic pathogens in order to define pathways of host resistance and their regulation. By so doing, we hope to design strategies for intervention against these infections in immunocompromised individuals. A secondary goal is to study the effects of the same pathogens on HIV-1 progression and to define the mechanisms involved. Significant progress was achieved this year in the following areas: 1) Identification of the dendritic cell as a major source of early T. gondii- induced IL-12. Cell fractionation and in situ staining experiments demonstrated that dendritic cells are likely to be the first host cells to produce IL-12 following T. gondii infection. 2) Identification of a novel transcription factor necessary for IL-12-dependent host resistance to T. gondii. The transcription factor ICSBP was shown to be required for control of T. gondii infection and to function by regulating the initial IL-12 response to the parasite. 3) Discovery of a latent form of T. gondii induced by vaccination. Immunization of mice with a tachyzoite extract plus IL-12 protected the animals from lethal challenge with a virulent strain. Nevertheless, the brains of these mice were found to contain latent parasite forms distinct from classical tissue cysts. 4) Development of a combined IL-12/antibiotic protocol for treatment of M. avium infection in vivo. Co-administration of IL-12 was shown to markedly enhance the efficacy of drug therapy of M. avium infections in mice.