ABSTRACT
In Chagas disease, CD8(+) T-cells are critical for the control of Trypanosoma cruzi during acute infection. Conversely, CD8(+) T-cell accumulation in the myocardium during chronic infection may cause tissue injury leading to chronic chagasic cardiomyopathy (CCC). Here we explored the role of CD8(+) T-cells in T. cruzi-elicited heart injury in C57BL/6 mice infected with the Colombian strain. Cardiomyocyte lesion evaluated by creatine kinase-MB isoenzyme activity levels in the serum and electrical abnormalities revealed by electrocardiogram were not associated with the intensity of heart parasitism and myocarditis in the chronic infection. Further, there was no association between heart injury and systemic anti-T. cruzi CD8(+) T-cell capacity to produce interferon-gamma (IFNγ) and to perform specific cytotoxicity. Heart injury, however, paralleled accumulation of anti-T. cruzi cells in the cardiac tissue. In T. cruzi infection, most of the CD8(+) T-cells segregated into IFNγ(+) perforin (Pfn)(neg) or IFNγ(neg)Pfn(+) cell populations. Colonization of the cardiac tissue by anti-T. cruzi CD8(+)Pfn(+) cells paralleled the worsening of CCC. The adoptive cell transfer to T. cruzi-infected cd8(-/-) recipients showed that the CD8(+) cells from infected ifnγ(-/-)pfn(+/+) donors migrate towards the cardiac tissue to a greater extent and caused a more severe cardiomyocyte lesion than CD8(+) cells from ifnγ(+/+)pfn(-/-) donors. Moreover, the reconstitution of naïve cd8(-/-) mice with CD8(+) cells from naïve ifnγ(+/+)pfn(-/-) donors ameliorated T. cruzi-elicited heart injury paralleled IFNγ(+) cells accumulation, whereas reconstitution with CD8(+) cells from naïve ifnγ(-/-)pfn(+/+) donors led to an aggravation of the cardiomyocyte lesion, which was associated with the accumulation of Pfn(+) cells in the cardiac tissue. Our data support a possible antagonist effect of CD8(+)Pfn(+) and CD8(+)IFNγ(+) cells during CCC. CD8(+)IFNγ(+) cells may exert a beneficial role, whereas CD8(+)Pfn(+) may play a detrimental role in T. cruzi-elicited heart injury.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Chagas Cardiomyopathy/immunology , Gene Expression Regulation/immunology , Interferon-gamma/immunology , Myocardium/immunology , Pore Forming Cytotoxic Proteins/immunology , Trypanosoma cruzi/immunology , Acute Disease , Animals , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/pathology , Cell Movement/genetics , Cell Movement/immunology , Chagas Cardiomyopathy/genetics , Chagas Cardiomyopathy/metabolism , Chagas Cardiomyopathy/pathology , Female , Gene Expression Regulation/genetics , Interferon-gamma/biosynthesis , Interferon-gamma/genetics , Male , Mice , Mice, Knockout , Myocardium/metabolism , Myocardium/pathology , Myocytes, Cardiac/immunology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Pore Forming Cytotoxic Proteins/biosynthesis , Pore Forming Cytotoxic Proteins/genetics , Trypanosoma cruzi/metabolismSubject(s)
Chagas Cardiomyopathy/etiology , Chagas Cardiomyopathy/immunology , Immunity/immunology , Receptors, Tumor Necrosis Factor/immunology , Tumor Necrosis Factor-alpha/immunology , Chagas Cardiomyopathy/genetics , Chagas Cardiomyopathy/prevention & control , Chronic Disease , Humans , Polymorphism, Genetic , Trypanosoma cruzi/immunology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/geneticsABSTRACT
One hundred years ago, Carlos Chagas discovered a new disease, the American trypanosomiasis. Chagas and co-workers later characterised the disease's common manifestation, chronic cardiomyopathy, and suggested that parasitic persistence coupled with inflammation was the key underlying pathogenic mechanism. Better comprehension of the molecular mechanisms leading to clinical heart afflictions is a prerequisite to developing new therapies that ameliorate inflammation and improve heart function without hampering parasite control. Here, we review recent data showing that distinct cell adhesion molecules, chemokines and chemokine receptors participate in anti-parasite immunity and/or detrimental leukocyte trafficking to the heart. Moreover, we offer evidence that CC-chemokine receptors may be attractive therapeutic targets aiming to regain homeostatic balance in parasite/host interaction thereby improving prognosis, supporting that it is becoming a non-phantasious proposal.
Subject(s)
Cell Adhesion Molecules/immunology , Chagas Cardiomyopathy/immunology , Myocarditis/immunology , Receptors, Chemokine/immunology , Trypanosoma cruzi/immunology , Animals , CD4-CD8 Ratio , Cell Movement , Chagas Cardiomyopathy/therapy , Chronic Disease , Myocarditis/parasitology , Trypanosoma cruzi/pathogenicityABSTRACT
One hundred years ago, Carlos Chagas discovered a new disease, the American trypanosomiasis. Chagas and co-workers later characterised the disease's common manifestation, chronic cardiomyopathy, and suggested that parasitic persistence coupled with inflammation was the key underlying pathogenic mechanism. Better comprehension of the molecular mechanisms leading to clinical heart afflictions is a prerequisite to developing new therapies that ameliorate inflammation and improve heart function without hampering parasite control. Here, we review recent data showing that distinct cell adhesion molecules, chemokines and chemokine receptors participate in anti-parasite immunity and/or detrimental leukocyte trafficking to the heart. Moreover, we offer evidence that CC-chemokine receptors may be attractive therapeutic targets aiming to regain homeostatic balance in parasite/host interaction thereby improving prognosis, supporting that it is becoming a non-phantasious proposal.