Sheltered in Stromal Tissue Cells, Trypanosoma cruzi Orchestrates Inflammatory Neovascularization via Activation of the Mast Cell Chymase Pathway

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Vellasco, Lucas ; Svensjo, Erik ; Bulant, Carlos Alberto ; Blanco, Pablo Javier ; Nogueira, Fabio ; Domont, Gilberto ; de Almeida, Natalia Pinto ; Nascimento, Clarissa Rodrigues ; Silva-dos-Santos, Danielle ; Carvalho-Pinto, Carla Eponina ; Medei, Emiliano Horacio ; Almeida, Igor C. ; Scharfstein, Julio

• Document type: Journal article
• Source: PATHOGENS; v. 11, n. 2, p. 29-pg., 2022-02-01.

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-IL1(3 and IFN-y). 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. (AU)

• FAPESP's process: 18/14221-2 - Coronary bifurcations geometry: an exploratory study of the mathematical laws to estimate the vascular dimensions in coronary bifurcations
• Grantee: Gabriela Hidalgo Vargas dos Santos
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 14/50889-7 - National Institute of Science and Technology Medicine Assisted by Scientific Computing (INCT-MACC)
• Grantee: José Eduardo Krieger
• Support Opportunities: Research Projects - Thematic Grants