# Polyphosphate and cardiac fibrosis by Trypanosoma cruzi

> **NIH NIH R21** · UNIVERSITY OF GEORGIA · 2023 · $188,750

## Abstract

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.

## Key facts

- **NIH application ID:** 10740934
- **Project number:** 1R21AI173402-01A1
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** ROBERTO DOCAMPO
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $188,750
- **Award type:** 1
- **Project period:** 2023-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10740934

## Citation

> US National Institutes of Health, RePORTER application 10740934, Polyphosphate and cardiac fibrosis by Trypanosoma cruzi (1R21AI173402-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10740934. Licensed CC0.

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