3-Hydroxy kynurenine treatment controls T. cruzi replication and the inflammatory pathology preventing the clinical symptoms of chronic Chagas disease

• Published in: PloS one 2011-10, Vol.6 (10), p.e26550-e26550
• Main Authors: Knubel, Carolina P, Martínez, Fernando F, Acosta Rodríguez, Eva V, Altamirano, Andrés, Rivarola, Héctor W, Diaz Luján, Cintia, Fretes, Ricardo E, Cervi, Laura, Motrán, Claudia C
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biology; Cardiomyopathy; Catabolites; Chagas disease; Chagas Disease - immunology; Chagas Disease - parasitology; Chagas Disease - prevention & control; Chronic Disease; Chronic illnesses; Chronic infection; Cloning; Coronary artery disease; Development and progression; Disease; EKG; Electrocardiography; Female; Fibrosis; Health aspects; Heart; Heart diseases; Immune clearance; Immune response; Immune system; Immunoregulation; Infection; Infections; Inflammation; Inflammation - drug therapy; Inflammation - immunology; Inflammation - parasitology; Inflammatory response; Interferon; Interferon-gamma - secretion; Kynurenine - analogs & derivatives; Kynurenine - pharmacology; Kynurenine - therapeutic use; Lesions; Lymphocytes; Lymphocytes T; Medical research; Medical treatment; Medicine; Mice; Mice, Inbred BALB C; Morphology; Parasitemia; Parasites; Pathogens; Pathology; Prevention; Protozoa; Replication; Skeletal muscle; Species Specificity; Stability; T cells; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - parasitology; Transforming growth factors; Trypanosoma cruzi; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - immunology; Trypanosoma cruzi - pathogenicity; Trypanosoma cruzi - physiology; Vector-borne diseases; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0026550

3-Hydroxy Kynurenine (3-HK) administration during the acute phase of Trypanosoma. cruzi infection decreases the parasitemia of lethally infected mice and improves their survival. However, due to the fact that the treatment with 3-HK is unable to eradicate the parasite, together with the known proapoptotic and immunoregulatory properties of 3-HK and their downstream catabolites, it is possible that the 3-HK treatment is effective during the acute phase of the infection by controlling the parasite replication, but at the same time suppressed the protective T cell response before pathogen clearance worsening the chronic phase of the infection. Therefore, in the present study, we investigated the effect of 3-HK treatment on the development of chronic Chagas' disease. In the present study, we treated mice infected with T. cruzi with 3-HK at day five post infection during 5 consecutive days and investigated the effect of this treatment on the development of chronic Chagas disease. Cardiac functional (electrocardiogram) and histopathological studies were done at 60 dpi. 3-HK treatment markedly reduced the incidence and the severity of the electrocardiogram alterations and the inflammatory infiltrates and fibrosis in heart and skeletal muscle. 3-HK treatment modulated the immune response at the acute phase of the infection impairing the Th1- and Th2-type specific response and inducing TGF-β-secreting cells promoting the emergence of regulatory T cells and long-term specific IFN-γ secreting cells. 3-HK in vitro induced regulatory phenotype in T cells from T. cruzi acutely infected mice. Our results show that the early 3-HK treatment was effective in reducing the cardiac lesions as well as altering the pattern of the immune response in experimental Chagas' disease. Thus, we propose 3-HK as a novel therapeutic treatment able to control both the parasite replication and the inflammatory response.