Abstract
Microangiopathy may worsen the clinical outcome of Chagas disease. Given the obstacles to investigating the dynamics of inflammation and angiogenesis in heart tissues parasitized by Trypanosoma cruzi, here we used intravital microscopy (IVM) to investigate microcirculatory alterations in the hamster cheek pouch (HCP) infected by green fluorescent protein-expressing T. cruzi (GFP-T. cruzi). IVM performed 3 days post-infection (3 dpi) consistently showed increased baseline levels of plasma extravasation. Illustrating the reciprocal benefits that microvascular leakage brings to the host-parasite relationship, these findings suggest that intracellular amastigotes, acting from inside out, stimulate angiogenesis while enhancing the delivery of plasma-borne nutrients and prosurvival factors to the infection foci. Using a computer-based analysis of images (3 dpi), we found that proangiogenic indexes were positively correlated with transcriptional levels of proinflammatory cytokines (pro-IL1β and IFN-γ). Intracellular GFP-parasites were targeted by delaying for 24 h the oral administration of the trypanocidal drug benznidazole. A classification algorithm showed that benznidazole (>24 h) blunted angiogenesis (7 dpi) in the HCP. Unbiased proteomics (3 dpi) combined to pharmacological targeting of chymase with two inhibitors (chymostatin and TY-51469) linked T. cruzi-induced neovascularization (7 dpi) to the proangiogenic activity of chymase, a serine protease stored in secretory granules from mast cells.
Highlights
Licensee MDPI, Basel, Switzerland.Chagas disease (CD), the chronic infection caused by the parasitic protozoan Trypanosoma cruzi, afflicts approximately 6–8 million people in Central and South America [1,2].Having diverged from T. brucei following the breakup of Gondwanaland ~100 millions of years ago [3], the South American trypanosomatid species evolved the ability to invade and develop intracellularly, in obligate manner
Decades after the disclosure of microcirculatory abnormalities in the heart autopsies of patients with chronic Chagas disease [60,61,62], it is still unclear whether the formation of dilated and tortuous microvessels in the myocardium might be a sequel of tissue parasitism and/or reflect collateral damage associated to T cell-dependent immunopathology
We used intravital microscopy (IVM) combined with proteomics and pharmacology to investigate the dynamics of inflammatory neovascularization in the parasitized hamster cheek pouch (HCP)
Summary
Chagas disease (CD), the chronic infection caused by the parasitic protozoan Trypanosoma cruzi, afflicts approximately 6–8 million people in Central and South America [1,2]. Having diverged from T. brucei following the breakup of Gondwanaland ~100 millions of years ago [3], the South American trypanosomatid species evolved the ability to invade and develop intracellularly, in obligate manner. It is currently subclassified into seven discrete typing units (DTU; TcI-TcVI and Tc-bat) [4,5]. Once released in fecal fluids, infective metacyclic trypomastigote forms invade susceptible cells in the lacerated skin tissues, or exposed oral/ocular mucosa, and/or enter the bloodstream. Tissue tropism and host-cell preference of T. cruzi vary considerably between different strains and genotypes [1,5], in vitro studies of trypomastigote interaction with cardiovascular cells demonstrated that parasite invasion is potentiated by interdependent signaling of
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