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Principal Investigator: Maria Pilar Aoki
Organization: NATIONAL RESEARCH COUNCIL OF ARGENTINA
Fiscal Year: 2024
Award: $130,912
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Chagas disease, a major public health problem in Latin America, is caused by the infection with the protozoan
parasite Trypanosoma (T.) cruzi and has been spread to non-endemic regions by migratory movements. Chagas
cardiomyopathy represents the most severe complication of chronic Chagas disease in Argentina. This important
illness has become a frequent cause of heart failure, cardio-embolic stroke, and sudden death in our and other
endemic countries. There are still no effective prophylactic vaccines, and chemotherapy mainly relies on
benznidazole, a 60-year-old drug linked to prolonged treatment and significant side effects. This parasite is an
obligate intracellular pathogen that can infect any nucleated cell, but the clinically relevant niches are the
cardiomyocytes since the parasite remains in the heart for several decades before the development of the
cardiomyopathy. Therefore, one of the main challenges in understanding Chagas disease immunopathology is
to find out why the parasite is not completely eliminated, being able to sustain a pathological inflammatory
environment. After infection, the influx of immune cells consumes large amounts of oxygen, and ischemic cells
rapidly respond to the hypoxic and inflammatory environment by releasing ATP to the extracellular milieu. This
extracellular ATP (eATP) triggers microbicidal immune responses but is quickly hydrolyzed to the potent
immunosuppressive metabolite adenosine, mainly via the concerted activity of CD39 and CD73 ectoenzymes.
Increasing evidence suggests that the balance of purinergic signaling determines the immune response's
outcome in different pathological scenarios. We hypothesize that the balance of purinergic responses to eATP
and the nucleosides generated by CD39 and CD73 determines anti-T. cruzi immunity and triggers pathogenic
mechanisms in Chagas disease. Hence, manipulating these signaling pathways could provide new approaches
to limiting cardiac pathology. The central hypothesis will be tested by pursuing three specific aims: 1) Validate
the participation of purinergic signaling in the cardiac response to T. cruzi infection in advanced human Chagas
disease, 2) Determine the impact of CD39-CD73 ectoenzymes on the cellular immune response, and the
progression of Chagas cardiomyopathy by employing experimental murine models, 3) Explore the benefits of
pharmacological targeting of purinergic signaling in a mouse model of Chagas cardiomyopathy. These
investigations will provide a comprehensive understanding of crucial mechanisms through which T. cruzi
infection subverts immune response to sustain parasite persistence and a detailed insight into the biology of the
cardiac response to infection.
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Terms: <Adenosine><American Trypanosomiasis><American trypanosome><Apoplexy><Argentina><Benznidazole><Biology><Blood leukocyte><Body Tissues><Brain Vascular Accident><Cardiac><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cardiomyopathies><Cardiomyopathy in Chagas' Disease><Cardiovascular Trypanosomiasis><Causality><Cell Body><Cell Communication and Signaling><Cell Density><Cell Isolation><Cell Lineage><Cell Mediated Immunology><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cell-Mediated Immunity><Cells><Cellular Immunity><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chagas Cardiomyopathy><Chagas Disease><Chagas Myocarditis><Chagas heart disease><Chronic><Cicatrix><Complication><Consumption><Country><Development><Disease Progression><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drugs><Environment><Equilibrium><Etiology><Experimental Models><Expression Signature><Fostering><Frequencies><Gene Expression Profile><Generalized Growth><Growth><Heart><Heart Muscle Cells><Heart failure><Heart myocyte><Human><Hypoxia><Hypoxic><Immune><Immune response><Immunes><Immunity><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunological response><Immunomodulation><Infection><Inflammatory Response><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigation><Ischemia><Knowledge><Latin America><Lesion><Leukocytes><Leukocytes Reticuloendothelial System><Link><Macrophage><Marrow leukocyte><Medication><Mice><Mice Mammals><Modeling><Modern Man><Movement><Murine><Mus><Myeloid Cells><Myocardial Diseases><Myocardial Disorder><Myocardiopathies><Myocarditis><Mφ><Nucleosides><O element><O2 element><Outcome><Oxygen><Oxygen Deficiency><Parasites><Particulate><Pathogenesis><Pathogenicity><Pathologic><Pathology><Pathway interactions><Patients><Pharmaceutical Preparations><Pharmacokinetics><Population><Preventative vaccine><Preventive vaccine><Prophylactic vaccine><Public Health><Purine Receptors><Purinergic Receptors><Purinoceptor><Regulatory Pathway><Reporting><Role><Scars><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><South American Trypanosomiasis><Sterility><Stroke><Sudden Death><System><T cruzi><T-Cells><T-Lymphocyte><T. cruzi><Testing><Time><Tissue Growth><Tissues><Transplant Recipients><Treatment Efficacy><Trypanosoma cruzi><VAC-TX><Vaccine Therapy><Validation><White Blood Cells><White Cell><affection><balance><balance function><benzonidazole><biological signal transduction><body movement><brain attack><cardiac chagas disease><cardiac failure><cardiac inflammation><cardiomyocyte><causation><cell sorting><cerebral vascular accident><cerebrovascular accident><chagasic cardiomyopathy><chemotherapy><clinical relevance><clinically relevant><developmental><disease causation><drug/agent><extracellular><gene expression pattern><gene expression signature><host response><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunopathology><immunoregulation><immunoregulatory><immunoresponse><improved><inflammatory environment><inflammatory milieu><insight><intervention efficacy><interventional strategy><microbicidal><microbicide><mouse model><murine model><myocardium disease><myocardium disorder><new approaches><novel><novel approaches><novel strategies><novel strategy><ontogeny><pathogen><pathway><pharmacologic><response><side effect><social role><sterile><stroked><strokes><therapeutic efficacy><therapeutic vaccination><therapy efficacy><thymus derived lymphocyte><transcriptional profile><transcriptional signature><transplant patient><validations><white blood cell><white blood corpuscle>