Evaluation of endothelial permeability to study dengue pathogenesis and screen compounds with therapeutic potential

• Grant number: 13/01702-9
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): November 01, 2015
• Effective date (End): June 30, 2019
• Field of knowledge: Biological Sciences - Microbiology
• Principal Investigator: Ester Cerdeira Sabino
• Grantee: Francielle Tramontini Gomes de Sousa
• Home Institution: Instituto de Medicina Tropical de São Paulo (IMT). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 17/16627-3 - Evaluation of the effects of the chemokines (CXCL1 and CXCL10) and the therapeutic potential of a sulfated glucomannan from Agaricus brasiliensis (MI-S) in severe dengue using in vitro and in vivo models of plasma leakage, BE.EP.PD

Abstract

The plasma leakage is one of the main signs of complication of dengue virus (DENV) infections and it is related to the disease severity. Dengue pathogenesis is complex and multifactorial, involving both viral and host factors. The lack of animal models representing satisfactorily the pathophysiology of dengue fever in humans has been limiting the advances in understanding the disease mechanisms as well as the development of drugs and vaccines for dengue management. Many studies have been shown that monocytes are one of the main cells responsible for immune response to infection with DENV, producing mediators that interact with endothelia and increasing vascular leakage in humans. Therefore, the aim of this project is to implement a model for assessing the in vitro vascular permeability using endothelial cells co-cultured with monocytes and infected by DENV in order to study the factors involved in vascular permeability and to screen compounds that possibly inhibit this process. The methodology involves the cultivation of endothelial cells on inserts with microporous membranes arranged in culture plates, generating two compartments, apical and basolateral. In this system, the cells infected with DENV can produce cytokines and mediators which will interfere with the in vitro vascular permeability, similarly to the in vivo mechanism. The vascular permeability will be calculated through the addition of fluorescent dextran at the apical site and measurement of its transport to the basolateral compartment. The proposed system will allow us to perform the screening of compounds with therapeutic potential against dengue and to study the interference of different clinical isolates of DENV on vascular permeability and the cytokine production profile in order to better understand the factors that interfere in the pathogenesis of severe dengue. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GOMES DE SOUSA CARDOZO, FRANCIELLE TRAMONTINI; BAIMUKANOVA, GYULNAR; LANTERI, MARION CHRISTINE; KEATING, SHEILA MARIE; FERREIRA, FREDERICO MORAES; HEITMAN, JOHN; PANNUTI, CLAUDIO SERGIO; PATI, SHIBANI; ROMANO, CAMILA MALTA; SABINO, ESTER CERDEIRA. Serum from dengue virus-infected patients with and without plasma leakage differentially affects endothelial cells barrier function in vitro. PLoS One, v. 12, n. 6 JUN 6 2017. Web of Science Citations: 8.