Role of Indoleamine 2,3-Dioxigenase (IDO) in the control of Trypanosoma cruzi experimental infection

KNUBEL, C; MARTINEZ, FERNANDO; DIAZ LUJAN, C; FRETES, R; MOTRAN, CC

Rio de Janeiro. Brasil

Congreso; 13th Internacional Congress of Immunology; 2007

IUIS

IDO is an intracellular enzyme that catalyses the initial rate-limiting step of tryptophan (Trp) catabolism that is constitutive expressed in several human and mouse cells. Its activity is up-regulated upon stimulation with proinflamatory mediators such as IFN-ã and TNF-á increasing the ability of IDO positive cells to inhibit the proliferation of intracellular pathogens through consumption of the essential amino acid Trp.  Recently an additional role for IDO as a natural inmmunoregulatory mechanism was proposed based on data showing that IDO is involved in the suppression of T cell response and in regulatory T cells induction. To determine the role of IDO in the control of T. cruzi infection, IDO expression was examined in BALB/c and B6 mice infected with 500 or 3000 trypomastigotes of Trypanosoma cruzi (Tulahuen strain) respectively along with the consequences of its blockade by in vivo treatment with an enzyme inhibitor (1-MT).  We found that sustained expression of IDO occurred in spleen, cardiac and skeletal muscle of both mice strains concomitantly with the infection.  IDO blockade impairs resistance to T. cruzi infection since 1-MT-treated mice showed significantly higher parasitemia levels (p<0.05) and lower survival rate than control group. In addition, IDO inhibition exacerbated the infection-associated heart inflammatory pathology without changes neither the regulatory T cells pool nor the specific humoral immune response. Our results suggest that in T. cruzi infection the IDO pathway participates mainly in the parasite replication control; however a possible role in the inflammatory and adaptative anti-parasite responses can not be rule out.