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Principal Investigator: Kathryn Marie Jones
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $781,984
Funding agency: National Institute of Allergy and Infectious Diseases
Mechanisms of myocarditis and progressive cardiac fibrosis in chronic Trypanosoma cruzi infection
Abstract:
Chagas disease, caused by infection with the vector borne intracellular protozoal parasite Trypanosoma cruzi,
affects approximately 6.5 million people worldwide. Chronic infection with T. cruzi results in persistent low grade
myocarditis and progressive fibrosis, which results in significant cardiac dysfunction called Chronic Chagasic
Cardiomyopathy (CCC). Patients with CCC have higher levels of cardiac inflammation, fibrosis, and circulating
inflammatory and fibrotic markers that correlate with disease severity. The antiparasitic drug benznidazole fails
to ameliorate the chronic inflammation and progressive fibrosis of CCC. Our long term goal is to define the
mechanisms of host inflammation, fibrosis and metabolic dysregulation in CCC in an effort to identify targets for
therapeutic interventions. T. cruzi induces host inflammatory and fibrotic pathways through multiple mechanisms.
Based on our knowledge of these mechanisms, we developed an immunotherapy consisting of the T. cruzi
derived antigen Tc24-C4 and a TLR4 agonist adjuvant. We previously showed that the immunotherapy, either
alone or combined with benznidazole in a vaccine-linked chemotherapy strategy, modulates host inflammatory
immune responses and results in reduced myocarditis and fibrosis. Additionally, we have shown that similar to
mouse models of lung, skin and liver fibrosis, inhibiting STAT3 activation with the small molecule TTI-101
significantly reduces cardiac fibrosis in a mouse model of CCC. This work led to our central hypothesis that
targeting host inflammatory and fibrotic pathways will synergize with anti-parasitic treatment to reduce cardiac
inflammation and fibrosis and improve cardiac health in CCC. Building on our preliminary data, we propose three
Specific Aims to evaluate efficacy of this combined treatment scheme: 1) Determine the effect of targeted
interventions (immunotherapy, benznidazole and TTI-101) on modulating parasite-induced inflammatory
immune responses; 2) Determine the effect of targeted interventions on modulating parasite-induced pro-fibrotic
response; and 3) Determine the effect of targeted interventions on modulating parasite-induced metabolic
responses. Through these aims, we will better define the pathogenesis of CCC, specifically the relative
contribution of host inflammatory, fibrotic, and metabolic dysregulation to disease progression. Targeted
interventions that restore the inflammatory, fibrotic and metabolic pathways to normal, and preserve cardiac
health, will help us identify key host response mechanisms that contribute to CCC. Additionally, these studies
will provide important proof of concept for developing multi-modal treatment strategies that target both the
parasite and underlying tissue pathologies of CCC to preserve cardiac health and ultimately improve clinical
outcomes.
Terms: <(TNF)-α><Address><Adjuvant><Affect><Agonist><American Trypanosomiasis><American trypanosome><Antigens><Antiparasitic Agents><Antiparasitic Drugs><Antiparasitics><Benznidazole><Body Tissues><Bone-Derived Transforming Growth Factor><CCN2><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CTGF><Cachectin><Cardiac><Cardiac health><Cardiomyopathy in Chagas' Disease><Cardiovascular Trypanosomiasis><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chagas Cardiomyopathy><Chagas Disease><Chronic><Clinical><Collagen><Combined Modality Therapy><Complementary intervention><Complementary therapies><Complementary treatment><Complex><Data><Deposit><Deposition><Development><Disease><Disease Progression><Disorder><Dose><ECG><EKG><Echocardiogram><Echocardiography><Electrocardiogram><Electrocardiography><Emulsions><Failure><Fibrosis><Fibrosis in the heart><Fibrosis in the myocardium><Fibrosis within the heart><Fibrosis within the myocardium><Fibrotic myocardium><Goals><Heart><Heart failure><Heart health><Homolog of Drosophila TOLL><IGF-binding protein-related protein-2><IGFBP-8><IGFBP-rP2><Imaging Procedures><Imaging Technics><Imaging Techniques><Immune mediated therapy><Immune response><Immunological response><Immunologically Directed Therapy><Immunotherapy><Infection><Infiltration><Inflammation><Inflammatory><Inflammatory Response><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Knowledge><Link><Liver Fibrosis><Lung Tissue Fibrosis><Macrophage-Derived TNF><Measures><Metabolic><Metabolic Pathway><Metabolic dysfunction><Mice><Mice Mammals><Milk Growth Factor><Monocyte-Derived TNF><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Myocardial depression><Myocardial dysfunction><Myocarditis><Neuropathy><Organ Preservation><Outcome><PDGF><Parasites><Parasiticides><Pathogenesis><Pathology><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Persons><Phosphorylation><Platelet Transforming Growth Factor><Platelet-Derived Growth Factor><Protein Phosphorylation><Proteins><Protozoa><Protozoal><Pulmonary Fibrosis><Recombinants><STAT1><STAT1 gene><STAT3><STAT3 gene><STAT91><Scheme><Severities><Severity of illness><Signal Transduction><Signal Transduction Systems><Signaling><South American Trypanosomiasis><Sudden Death><T cruzi><T. cruzi><T8 Cells><T8 Lymphocytes><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><TLR4><TLR4 gene><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Therapeutic Intervention><Time><Tissues><Toll Homologue><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Transthoracic Echocardiography><Trypanosoma cruzi><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Tyrosine Phosphorylation><Vaccines><Vascular Diseases><Vascular Disorder><Work><acylcarnitine><benzonidazole><biological signal transduction><blood vessel disorder><cardiac dysfunction><cardiac failure><cardiac fibrosis><cardiac function><cardiac imaging><cardiac inflammation><cardiac metabolism><cardiac preservation><cardiac scanning><chagasic cardiomyopathy><chemotherapy><chronic infection><combination therapy><combined modality treatment><combined treatment><connective tissue growth factor><coronary fibrosis><cutaneous fibrosis><cytokine><dermal fibrosis><determine efficacy><developmental><disease severity><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><fibrosis in the lung><fibrotic heart><fibrotic liver><fibrotic skin><fisp12 protein><function of the heart><heart dysfunction><heart fibrosis><heart function><heart imaging><heart metabolism><heart preservation><heart scanning><heart sonography><hepatic fibrosis><host response><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunoresponse><improved><inflammation marker><inflammatory marker><insulin-like growth factor binding protein 8><intervention effect><intervention therapy><interventional strategy><lung fibrosis><mouse model><multi-modal therapy><multi-modal treatment><murine model><myocardial fibrosis><neuropathic><parasite invasion><pathway><patient oriented outcomes><persistent infection><response><skin fibrosis><small molecule><synergism><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><toll-like receptor 4><treatment strategy><vascular dysfunction><vasculopathy><vector-borne><vectorborne>