CIBICI   14215
CENTRO DE INVESTIGACION EN BIOQUIMICA CLINICA E INMUNOLOGIA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Indoleamine 2,3-dioxigenase (IDO) is essential for the control of T. cruzi amastigote growth in macrophages
Autor/es:
KNUBEL, C; MARTINEZ, FERNANDO; DIAZ LUJAN, C; FRETES, R; MOTRAN, CLAUDIA CRISTINA
Lugar:
Mar del Plata
Reunión:
Congreso; . LVII Reunión Científica Anual de la Sociedad Argentina de Inmunologia y LVI Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica; 2009
Institución organizadora:
SAI-SAIC
Resumen:
Indoleamine 2,3-dioxigenase (IDO) is essential for the control of T. cruzi amastigote growth in macrophages.   Carolina P. Knubel, Fernando F. Martínez, Cintia Díaz Lujan, Ricardo Fretes and 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 dependent on the capacity to generate IFN-g and TNF which can activate macrophages (Mo) to produce the microbicidal product nitric oxide (NO) by NO synthase (iNOS). In addition, these proinflammatory cytokines are able to induce IDO activity in Mo. IDO is an intracellular enzyme that catalyses the initial step of tryptophan (Trp) catabolism leading to the production of immunoregulatory catabolites, collectively called “kynurenines”.  Depletion of Trp and the production of “kynurenines” are responsible for the activities observed after IDO induction including inhibition of intracellular pathogens replication and lymphocyte proliferation and Treg induction.  We demonstrated that in vivo IDO blockade impairs the resistance of mice to T. cruzi infection.  To study the effect of IDO activity on the regulation of intracellular T cruzi growth, we used murine bone marrow derived Mo.  IDO blockade by 1-MT resulted in a strong induction of parasite growth.  Trp supplementation promoted T. cruzi replication but to levels that were lower than those observed in 1-MT-treated cultures. Moreover, the supplementation with the kynurenine (Kyn) downstream metabolite 3-HK but not Kyn, 3-HAA or QA inhibited the intracellular parasite replication.  However, 3-HK, 3-HAA and QA were all able to reduce the intracellular parasite replication in cultures with 1-MT. We also observed that 3-HK acted by a direct trypanocidal activity rather than by inducing Mo activation. To study the contribution of inducible IDO and iNOS to control T. cruzi replication, Mo were cultured in medium alone or containing IFN-g plus LPS for 24 h and then infected.  The activation with INF-g plus LPS resulted in iNOS and IDO activity up-regulation and a strong inhibitory effect of parasite growth that was reversed in presence of 1-MT.  IDO activity, through the production of Trp catabolites, is essential for the control of T. cruzi replication in Mo.