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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

Grant number: 17/16627-3
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): March 01, 2018
Effective date (End): February 28, 2019
Field of knowledge:Biological Sciences - Microbiology
Principal Investigator:Ester Cerdeira Sabino
Grantee:Francielle Tramontini Gomes de Sousa
Supervisor abroad: Eva Harris
Home Institution: Instituto de Medicina Tropical de São Paulo (IMT). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Local de pesquisa : University of California, Berkeley (UC Berkeley), United States  
Associated to the scholarship:13/01702-9 - Evaluation of endothelial permeability to study dengue pathogenesis and screen compounds with therapeutic potential, BP.PD

Abstract

Plasma leakage is one of the main complications of dengue virus (DENV) infections and is directly related to disease severity. Dengue pathogenesis is complex and multifactorial, involving both viral and host factors. We have recently showed that contact of endothelial cells with serum from DENV-infected patients with leakage disrupts endothelial barrier function, indicated by reduction of Transendothelial Electric Resistance (TEER), more significantly than serum from DENV-infected patients without leakage. The serum levels of some immunomediators, including CXCL1, EGF, eotaxin, IFN-³, and sCD40L, as well as platelets, were significantly decreased in the leakage group, while IL-10, IL-6, and CXCL10 (IP-10) levels were significantly increased. Of these, CXCL1, CXCL10, and platelet levels were strongly correlated with TEER values. These results have stimulated us to further study the role of CXCL1 and CXCL10 on endothelial homeostasis during DENV infection. Agaricus brasiliensis (syn A. subrufescens) is a basidiomycete fungus native to Brazil. Its mycelial cell wall is rich in (1,3)-beta-D-gluco-(1,2)-beta-D-mannan, which was chemically modified to produce its sulfated derivative (MI-S). Endothelial glycocalyx layer (EGL) degeneration is one of the mechanisms of plasma leakage occurring in DENV-infected individuals, as described recently by Dr. Eva Harris' team. Since sulfated polysaccharides can interact with the glycocalyx layer, increasing its homeostatic properties, their therapeutic potential to manage severe dengue must be assessed. In fact, our preliminary results show that MI-S treatment significantly inhibited TEER reduction induced by contact with DENV-2- or DENV-4-infected monocytes in comparison to medium-treated controls. These results suggest that MI-S may have an in vivo anti-leak effect. Further experiments are warranted to investigate the mechanism of the in vitro detected activity and assess its effects in a mouse model so as to determine the therapeutic potential of MI-S. Therefore, the aim of this project is to evaluate the effects of the chemokines CXCL1 and CXCL10 and the therapeutic potential of MI-S in severe dengue using in vitro and in vivo models of vascular leakage. Given the substantial expertise of Dr. Eva Harris in various aspects of dengue disease, particularly mechanistic approaches to study plasma leakage in vitro and in vivo, the collaboration between the proponents of this project and Dr. Harris' group would be essential to achieve the proposed objectives.