Central nervous system toxoplasmosis has caused disability and death in up to 30% of patients with AIDS. Current clinical treatment for toxoplasma infection is mainly chemotherapeutical, which is often associated with dose-related bone marrow suppression. Complete remission of the infection depends largely on the adequate restoration of the cell-mediated immune system of the patients and thus, it poses a continuous threat to AIDS patients. An alternative treatment using recombinant interferon-gamma (IFN-gamma) has been proposed since IFN- gamma, a CD4+ T cell product, blocks the growth of T gondii in a variety of tissues and cells. This IFN-gamma-mediated anti-toxoplasmic activity is strongly correlated with the degradation of the essential amino acid L-tryptophan in vitro. Destruction of L-tryptophan is due to the increased activity of indoleamine 2,3-dioxygenase (IDO) which is in turn transcriptionally activated by IFN-gamma. It has been suggested that T gondii infection is primarily controlled by IDO activity induced by IFN- gamma derived from CD4+ T lymphocytes. Therefore, we propose to investigate the role of IDO in host defense against T gondii infection, and specifically to determine whether IDO activity alone, expressed via stable transfection of IDO cDNA controlled by a metallothionein inducible promoter, blocks the growth of T gondii in cultured human fibroblasts and macrophage cell line. Elucidation of the role of IDO in blocking T gondii replication will provide not only host defense mechanism but also new concept for developing effective drugs for prevention and treatment of toxoplasmosis in AIDS patients.
| Gupta, S L; Carlin, J M; Pyati, P et al. (1994) Antiparasitic and antiproliferative effects of indoleamine 2,3-dioxygenase enzyme expression in human fibroblasts. Infect Immun 62:2277-84 |
