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Principal Investigator: ROBERTO DOCAMPO
Organization: UNIVERSITY OF GEORGIA
Fiscal Year: 2023
Award: $188,750
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
Cardiomyopathy is the most frequent clinical manifestation of Chagas disease. The pathogenesis of the
heart disease is attributed to the persistence of T. cruzi leading to chronic inflammation, fibrosis, cardiac
hypertrophy and heart failure. Fibrosis results from excessive accumulation of extracellular matrix (ECM)
by terminally differentiated fibroblast (myofibroblasts) in response to injury or illness and leads to organ
disfunction and failure. Interstitial fibrosis occurs in both acute and chronic myocarditis caused by T. cruzi,
and is characterized by the deposition of ECM components. The parasite per se appears to be responsible
since deposition of ECM components (fibronectin, laminin, and collagen) also occurs in cultures of cardiac
myofibroblasts infected by the parasite, where no inflammatory cells are present, and is reversible upon
treatment with the trypanocidal agent posaconazole. Recent work has discovered that polyphosphate
(polyP), acting as a cell signaling molecule, is a potent inducer of fibroblast chemotaxis, myofibroblast
differentiation, and production of ECM components, such as a-smooth muscle actin, stress fibers, and
collagen. We have found that polyP is released by cells such as platelets, and mast cells. PolyP is
abundantly present in all life cycle stages of T. cruzi, reaching cellular mM concentrations, and is located in
acidocalcisomes, glycosomes, nucleoli, and in the outer surface of the parasite. It is not known whether
polyP is also released from T. cruzi although the parasite is able to release extracellular vesicles budding
from the plasma membrane, and the localization of polyP in the outer surface of the parasite suggest that it
is. In summary, there is evidence that: (1) T. cruzi per se stimulates fibroblast to myofibroblast transition
and deposition of ECM components; (2) deposition of ECM components by T. cruzi-infected cardiac
myofibroblasts occurs in the absence of inflammatory cells, (3) polyP is involved in fibroblast chemotaxis,
myofibroblast differentiation, and production of ECM components; and (4) polyP is abundant in T. cruzi and
expressed in the outer surface of the cells and is released in extracellular vesicles (EVs). We will explore
two hypotheses that are related to our recent findings: 1. That T. cruzi surface or released polyP stimulates
fibrosis; and 2. That T. cruzi surface or released polyP is involved in the deposition of ECM components by
myofibroblasts through the activation of signaling cascades.
Terms: <Actins><Acute Myocarditis><Address><Adhesives><Affect><American Trypanosomiasis><American trypanosome><Americas><Binding><Blood Neutrophil><Blood Platelets><Blood Polymorphonuclear Neutrophil><Body Tissues><Cardiac><Cardiac Diseases><Cardiac Disorders><Cardiomyopathies><Causality><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell membrane><Cell surface><Cell-Extracellular Matrix><Cells><Cessation of life><Chagas Disease><Chemotaxis><Chronic><Cicatrix><Clinical><Cold-Insoluble Globulins><Collagen><Cytoplasmic Membrane><Death><Deposit><Deposition><Development><Drug Therapy><Dysfunction><ECM><Elastin><Etiology><Extracellular Matrix><FN1><Failure><Fiber><Fibroblasts><Fibronectin 1><Fibronectins><Fibrosis><Functional disorder><Generations><Glycoprotein GP-2><Glycosome><Heart Diseases><Heart Hypertrophy><Heart failure><Infection><Inflammation><Inflammatory><Intracellular Communication and Signaling><Involuntary Muscle><LETS Proteins><Laminin><Large External Transformation-Sensitive Protein><Life Cycle><Life Cycle Stages><Malignant Cell><Marrow Mast Cell><Marrow Neutrophil><Marrow platelet><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Molecular><Molecular Interaction><Myocardial Diseases><Myocardial Disorder><Myocardiopathies><Myofibroblast><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Opsonic Glycoprotein><Opsonic alpha(2)SB Glycoprotein><Organ><Orthophosphate><Parasites><Pathogenesis><Pathogenicity><Pathology><Persons><Pharmacotherapy><Physiopathology><Plasma Membrane><Platelets><Polymers><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Polyphosphates><Polyps><Production><Proteins><Proteoglycan><Role><Scars><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Smooth Muscle><South American Trypanosomiasis><Stimulant><Stress Fibers><Structural Protein><Surface><Surface Proteins><T cruzi><T. cruzi><Thrombocytes><Time><Tissue Basophils><Tissues><Trypanocidal Agents><Trypanocidal Drugs><Trypanocides><Trypanosoma cruzi><Trypanosomicidal Agents><Trypanosomicides><Vesicle><Work><access to vaccination><access to vaccines><alpha 2-Surface Binding Glycoprotein><biological signal transduction><cancer cell><cardiac failure><cardiac fibrosis><cardiac hypertrophy><causation><chronic myocarditis><coronary fibrosis><developmental><disease causation><drug treatment><experiment><experimental research><experimental study><experiments><extracellular><extracellular vesicles><flexibility><flexible><heart disorder><injury response><interstitial><life course><mast cell><mastocyte><myocardial fibrosis><myocardium disease><myocardium disorder><neutrophil><pathophysiology><plasmalemma><polymer><polymeric><posaconazole><prevent><preventing><response to injury><side effect><social role><vaccination access><vaccination availability><vaccine access><vaccine availability>