Sulfated beta-glucan from Agaricus subrufescens inhibits flavivirus infection and nonstructural protein 1-mediated pathogenesis

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de Sousa, Francielle Tramontini Gomes ; Biering, Scott B. ; Patel, Trishna S. ; Blanc, Sophie F. ; Camelini, Carla M. ; Venzke, Dalila ; Nunes, Ricardo J. ; Romano, Camila M. ; Beatty, P. Robert ; Sabino, Ester C. ; Harris, Eva

• Document type: Journal article
• Source: Antiviral Research; v. 203, p. 9-pg., 2022-05-18.

Abstract

Despite substantial morbidity and mortality, no therapeutic agents exist for treatment of dengue or Zika, and the currently available dengue vaccine is only recommended for dengue virus (DENV)-immune individuals. Thus, development of therapeutic and/or preventive drugs is urgently needed. DENV and Zika virus (ZIKV) nonstructural protein 1 (NS1) can directly trigger endothelial barrier dysfunction and induce inflammatory re-sponses, contributing to vascular leak in vivo. Here we evaluated the efficacy of the (1-6,1-3)-beta-D-glucan isolated from Agaricus subrufescens fruiting bodies (FR) and its sulfated derivative (FR-S) against DENV-2 and ZIKV infection and NS1-mediated pathogenesis. FR-S, but not FR, significantly inhibited DENV-2 and ZIKV replication in human monocytic cells (EC50 = 36.5 and 188.7 mu g/mL, respectively) when added simultaneously with viral infection. No inhibitory effect was observed when FR or FR-S were added post-infection, suggesting inhibition of viral entry as a mechanism of action. In an in vitro model of endothelial permeability using human pulmonary microvascular endothelial cells (HPMECs), FR and FR-S (0.12 mu g/mL) inhibited DENV-2 NS1-and ZIKV NS1-induced hyperpermeability by 50% and 100%, respectively, as measured by Trans-Endothelial Electrical Resistance. Treatment with 0.25 mu g/mL of FR and FR-S inhibited DENV-2 NS1 binding to HPMECs. Further, FR-S significantly reduced intradermal hyperpermeability induced by DENV-2 NS1 in C57BL/6 mice and protected against DENV-induced morbidity and mortality in a murine model of dengue vascular leak syndrome. Thus, we demonstrate efficacy of FR-S against DENV and ZIKV infection and NS1-induced endothelial permeability in vitro and in vivo. These findings encourage further exploration of FR-S and other glycan candidates for flavivirus treatment alone or in combination with compounds with different mechanisms of action. (AU)

• FAPESP's process: 13/01690-0 - Establishment of an in vitro model of vascular permeability evaluation to study the hemorrhagic dengue fever pathogenesis and screening of compounds with therapeutic potential
• Grantee: Ester Cerdeira Sabino
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/01702-9 - Evaluation of endothelial permeability to study dengue pathogenesis and screen compounds with therapeutic potential
• Grantee: Francielle Tramontini Gomes de Sousa
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 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
• Grantee: Francielle Tramontini Gomes de Sousa
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor