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

Abstract

Background: 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. Principal Findings: 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. Conclusions: 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. © 2011 Knubel et al.