Polyphosphate and cardiac fibrosis by Trypanosoma cruzi

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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.