Indoleamine 2,3-dioxigenase (IDO) is critical for host resistance against Trypanosoma cruzi.
Indoleamine 2,3-dioxygenase (IDO) is an inflammatory cytokine-inducible rate-limiting enzyme of the tryptophan (Trp) catabolism, which is involved in the inhibition of intracellular pathogen replication as well as in immunomodulation. Here we demonstrated the effect of IDO-dependent Trp catabolism on Trypanosoma cruzi resistance to acute infection. Infection with T. cruzi resulted in the systemic activation of IDO. The blocking of IDO activity in vivo impaired resistance to the infection and exacerbated the parasite load and infection-associated pathology. In addition, IDO activity was critical to controlling the parasite's replication in macrophages (Mos), despite the high production of nitric oxide produced by IDO-blocked T. cruzi-infected Mos. Analysis of the mechanisms by which IDO controls the parasite replication revealed that T. cruzi amastigotes were sensitive to L-kynurenine downstream metabolites 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranilic acid, while 3-HK also affected the trypomastigote stage. Finally, 3-HK treatment of mice acutely infected with T. cruzi was able to control the parasite and to improve the survival of lethally infected mice. During infection, IDO played a critical role in host defense against T. cruzi; therefore, the intervention of IDO pathway could be useful as a novel antitrypanosomatid therapeutic strategy.
Centro de Investigaciones en Bioquímica Clínica e Inmunología-Consejo Nacional de Investigaciones Científicas y Tecnicas, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, 5000, Argentina.
Carolina Paola
CP
Knubel
Fernando Fabián
FF
Martínez
Ricardo E
RE
Fretes
Cintia
C
Díaz Lujan
Martín Gustavo
MG
Theumer
Laura
L
Cervi
Claudia Cristina
CC
Motrán
D015095:3-Hydroxyanthranilic Acid; D000818:Animals; D014355:Chagas Disease / Q000276:immunology; D006790:Host-Parasite Interactions / Q000276:immunology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology / Q000502:physiology*; D007737:Kynurenine / Q000031:analogs & derivatives; D008264:Macrophages / Q000201:enzymology / Q000469:parasitology; D051379:Mice; D014349:Trypanosoma cruzi / Q000276:immunology* / Q000502:physiology
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D015095:3-Hydroxyanthranilic Acid; C005045:3-hydroxykynurenine; D007737:Kynurenine