Indoleamine 2,3-dioxigenase (IDO) is important for the control of T. cruzi amastigote growth in macrophages

KNUBEL, C; MARTINEZ, FERNANDO; MOTRAN, CLAUDIA CRISTINA

Armacao dos Buzios, RJ, Brasil.

Congreso; XIII Intenational Congress of Protistology. XXXVI Annual Meeting on Basic Research in Chagas’s disease. XXV Annual Meeting of the Brazilian Society of Protozoology.; 2009

Brazilian Society of Protozoology

Indoleamine 2,3-dioxigenase (IDO) is important for the control of T. cruzi amastigote growth in macrophages.   Carolina P. Knubel, Fernando F. Martinez, Claudia C Motran*. Clinical Biochemical Department. CIBICI-CONICET. Chemical Sciences Faculty. National University of Cordoba. *cmotran@fcq.unc.edu.ar   Resistance to T. cruzi infection is reported to be dependent on the capacity to generate IFN-g and TNF which can activate macrophages (Mo) to produce the microbicidal product nitric oxide (NO) generated by NO synthase (iNOS). In addition, these proinflammatory cytokines are able to induce IDO activity in Mo and dendritic cells. IDO is an intracellular enzyme that catalyses the initial rate-limiting step of tryptophan (Trp) catabolism leading to the production of immunoregulatory catabolites, collectivelly called “kynurenines”.  Depletion of Trp and the production of “kynurenines” are responsible for the activities observed after IDO induction including effects on intracellular pathogens replication and lymphocyte proliferation, survival and anergy.  We have demonstrated that in vivo IDO blockade using 1-MT impairs the resistance to T. cruzi infection in mice.  In order to study the effect of IDO activity on the regulation of intracellular T cruzi growth, we used murine bone marrow derived Mo.  IDO blockade in Mo resulted in a strong stimulatory effect on parasite growth that was dependent of 1-MT dose.  In addition, Trp supplementation could prevent IDO-mediated inhibition meanwhile the addition of L-kynurenine has no effect on parasite replication. In order to know the specific contribution of IFN-g-inducible IDO and iNOS to control T. cruzi replication, Mo were cultured in medium alone or containing IFN-g or IFN-g plus LPS for 24 h and then infected.  The activation with INF-g or INF-g plus LPS resulted in NO production, induction of IDO activity and a strong inhibitory effect of amastigote growth. Moreover, the IDO blockade in these cultures resulted in a reversion of the inhibitory effect of amastigotes growth induced by IFN-g or IFN-g plus LPS.  IDO activity, through Trp starvation, is critical for the control of T. cruzi amastigote growth in Mo. Supported by ANPCyT, CONICET and Secyt-UNC.