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Indoleamine 2,3‐dioxigenase (IDO) is critical for host resistance against Trypanosoma cruzi
Author(s) -
Knubel Carolina Paola,
Martínez Fernando Fabián,
Fretes Ricardo E.,
Lujan Cintia Díaz,
Theumer Martín Gustavo,
Cervi Laura,
Motrán Claudia Cristina
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-150920
Subject(s) - trypanosoma cruzi , chagas disease , biology , kynurenine , pathogen , immunology , parasite hosting , indoleamine 2,3 dioxygenase , microbiology and biotechnology , virology , tryptophan , biochemistry , amino acid , world wide web , computer science
Indoleamine 2,3‐dioxigenase (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.—Knubel, C. P., Martínez, F. F., Fretes, R. E., Díaz Lujan, C., Theumer, M. G., Cervi, L., Motran, C. C. Indoleamine 2,3‐dioxigenase (IDO) is critical for host resistance against Trypanosoma cruzi . FASEB J . 24, 2689–2701 (2010). www.fasebj.org