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


RESULTS
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.
Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Universidad Nacional de Córdoba, Ciudad Universitaria, Córdoba, Argentina.
Carolina P
CP
Knubel
Fernando F
FF
Martínez
Eva V
EV
Acosta Rodríguez
Andrés
A
Altamirano
Héctor W
HW
Rivarola
Cintia
C
Diaz Luján
Ricardo E
RE
Fretes
Laura
L
Cervi
Claudia C
CC
Motrán
D000818:Animals; D014355:Chagas Disease / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control*; D002908:Chronic Disease; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000469:parasitology; D007371:Interferon-gamma / Q000378:metabolism; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D013045:Species Specificity; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology*
C005045:3-hydroxykynurenine; D007737:Kynurenine; D007371:Interferon-gamma