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Title: HUMAN INDOLEAMINE 2,3-DIOXYGENASE INHIBITS TOXOPLASMA GONDII GROWTH IN FIBROBLAST CELLS

Author
item DAI WEI - HIPPLE CANCER RES CTR, OH
item PAN HUIQI - HIPPLE CANCER RES CTR, OH
item Kwok, Oliver
item Dubey, Jitender

Submitted to: Journal of Interferon Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/20/1994
Publication Date: N/A
Citation: N/A

Interpretive Summary: Infection by the protozoan (single celled) parasite Toxoplasma gondii is widespread in livestock and humans. It causes mental retardation and loss of vision in children and abortion in livestock. There is no effective vaccine for humans or animals. There are no drugs that eliminate the parasite from the body, especially in AIDS patients. It is estimated that 10% of all AIDS patients die of toxoplasmosis. Interferon is a substance naturally liberated from host cells. Interferon-gamma is known to inhibit the growth of Toxoplasma in cell culture as well as in patients infected with T. gondii. Scientists at the Beltsville Agricultural Research Center and the Hipple Cancer Research Center have characterized the gene for the enzyme that mediates action of interferon-gamma on T. gondii. These studies are likely to be helpful in developing effective resistance against Toxoplasma parasites.

Technical Abstract: Interferon-gamma is known to inhibit the growth of Toxoplasma gondii both in vivo and in vitro. The IFN-gamma-induced anti- toxoplasma activity in human cells is strongly correlated with the degradation of the essential amino acid L-tryptophan in vitro. Destruction of L-tryptophan is due to an increased activity of indoleamine 2,3-dioxygenase (INDO) which is transcriptionally activated by IFN-gamma. To determine if indoleamine 2,3-dioxygenase alone is sufficient to block the T. gondii growth, we transfected human fibroblast cells with an INDO cDNA expression plasmid using metallothionein-inducible promoter. We showed that INDO mRNA and its enzymatic activity are inducible in fibroblast cells transfected with right-orientation INDO cDNA upon addition of CdCL2 to culture medium. The elevated INDO enzyme activity is strongly correlated with an inhibition of T. gondii growth. No INDO mRNA nor enzyme activity is induced by CdCl2 in reverse orientation transfected cells, and no adverse effects were observed on T. gondii growth in cells transfected with the reverse INDO-construct or in control parent cells with or without supplementation of CdCl2. These data all suggest that IFN-gamma-induced anti-toxoplasma activity is due at least in part to the activation of INDO gene.