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Sulfated β-glucan from Agaricus subrufescens inhibits flavivirus infection and nonstructural protein 1-mediated pathogenesis
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 Z...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10416543/ https://www.ncbi.nlm.nih.gov/pubmed/35533778 http://dx.doi.org/10.1016/j.antiviral.2022.105330 |
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author | 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 |
author_facet | 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 |
author_sort | de Sousa, Francielle Tramontini Gomes |
collection | PubMed |
description | 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 (EC(50) = 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. |
format | Online Article Text |
id | pubmed-10416543 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
record_format | MEDLINE/PubMed |
spelling | pubmed-104165432023-08-11 Sulfated β-glucan from Agaricus subrufescens inhibits flavivirus infection and nonstructural protein 1-mediated pathogenesis 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 Antiviral Res Article 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 (EC(50) = 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. 2022-07 2022-05-06 /pmc/articles/PMC10416543/ /pubmed/35533778 http://dx.doi.org/10.1016/j.antiviral.2022.105330 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ). |
spellingShingle | Article 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 Sulfated β-glucan from Agaricus subrufescens inhibits flavivirus infection and nonstructural protein 1-mediated pathogenesis |
title | Sulfated β-glucan from Agaricus subrufescens inhibits flavivirus infection and nonstructural protein 1-mediated pathogenesis |
title_full | Sulfated β-glucan from Agaricus subrufescens inhibits flavivirus infection and nonstructural protein 1-mediated pathogenesis |
title_fullStr | Sulfated β-glucan from Agaricus subrufescens inhibits flavivirus infection and nonstructural protein 1-mediated pathogenesis |
title_full_unstemmed | Sulfated β-glucan from Agaricus subrufescens inhibits flavivirus infection and nonstructural protein 1-mediated pathogenesis |
title_short | Sulfated β-glucan from Agaricus subrufescens inhibits flavivirus infection and nonstructural protein 1-mediated pathogenesis |
title_sort | sulfated β-glucan from agaricus subrufescens inhibits flavivirus infection and nonstructural protein 1-mediated pathogenesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10416543/ https://www.ncbi.nlm.nih.gov/pubmed/35533778 http://dx.doi.org/10.1016/j.antiviral.2022.105330 |
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