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

• DOI: 10.1016/j.antiviral.2022.105330
• Publication Date: 2022-05-06T15:14:52Z
• Authors: Francielle Tramon...; Scott B. Biering; Trishna S. Patel; Sophie F. Blanc; Carla M. Camelini; Dalila Venzke; Ricardo J. Nunes; Camila M. Romano; P. Robert Beatty; Ester C. Sabino; Eva Harris
• Keywords: 0301 basic medicine; beta-Glucans; Agaricus; 610; Viral Nonstructural Proteins; Inbred C57BL; Antibodies, Viral; Dengue virus; Antibodies; Article; Zika virus; Dengue; Mice; 03 medical and health sciences; Animals; Viral; Sulfated polysaccharides; Vascular leak; Sulfates; Zika Virus Infection; Flavivirus; Endothelial Cells; Zika Virus; Dengue Virus; Nonstructural protein 1; 3. Good health; Mice, Inbred C57BL

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 responses, contributing to vascular leak in vivo. Here we evaluated the efficacy of the (1-6,1-3)-β-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 μg/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 μg/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 μg/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.