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Berbamine suppresses intestinal SARS-CoV-2 infection via a BNIP3-dependent autophagy blockade
SARS-CoV-2, the causative virus of COVID-19, continues to threaten global public health. COVID-19 is a multi-organ disease, causing not only respiratory distress, but also extrapulmonary manifestations, including gastrointestinal symptoms with SARS-CoV-2 RNA shedding in stool long after respiratory...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10114999/ https://www.ncbi.nlm.nih.gov/pubmed/36951188 http://dx.doi.org/10.1080/22221751.2023.2195020 |
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author | Cloherty, Alexandra P. M. Rader, Anusca G. Patel, Kharishma S. Pérez-Vargas, Jimena Thompson, Connor A. H. Ennis, Siobhan Niikura, Masahiro Wildenberg, Manon E. Muncan, Vanesa Schreurs, Renée R. C. E. Jean, François Ribeiro, Carla M. S. |
author_facet | Cloherty, Alexandra P. M. Rader, Anusca G. Patel, Kharishma S. Pérez-Vargas, Jimena Thompson, Connor A. H. Ennis, Siobhan Niikura, Masahiro Wildenberg, Manon E. Muncan, Vanesa Schreurs, Renée R. C. E. Jean, François Ribeiro, Carla M. S. |
author_sort | Cloherty, Alexandra P. M. |
collection | PubMed |
description | SARS-CoV-2, the causative virus of COVID-19, continues to threaten global public health. COVID-19 is a multi-organ disease, causing not only respiratory distress, but also extrapulmonary manifestations, including gastrointestinal symptoms with SARS-CoV-2 RNA shedding in stool long after respiratory clearance. Despite global vaccination and existing antiviral treatments, variants of concern are still emerging and circulating. Of note, new Omicron BA.5 sublineages both increasingly evade neutralizing antibodies and demonstrate an increased preference for entry via the endocytic entry route. Alternative to direct-acting antivirals, host-directed therapies interfere with host mechanisms hijacked by viruses, and enhance cell-mediated resistance with a reduced likelihood of drug resistance development. Here, we demonstrate that the autophagy-blocking therapeutic berbamine dihydrochloride robustly prevents SARS-CoV-2 acquisition by human intestinal epithelial cells via an autophagy-mediated BNIP3 mechanism. Strikingly, berbamine dihydrochloride exhibited pan-antiviral activity against Omicron subvariants BA.2 and BA.5 at nanomolar potency, providing a proof of concept for the potential for targeting autophagy machinery to thwart infection of current circulating SARS-CoV-2 subvariants. Furthermore, we show that autophagy-blocking therapies limited virus-induced damage to intestinal barrier function, affirming the therapeutic relevance of autophagy manipulation to avert the intestinal permeability associated with acute COVID-19 and post-COVID-19 syndrome. Our findings underscore that SARS-CoV-2 exploits host autophagy machinery for intestinal dissemination and indicate that repurposed autophagy-based antivirals represent a pertinent therapeutic option to boost protection and ameliorate disease pathogenesis against current and future SARS-CoV-2 variants of concern. |
format | Online Article Text |
id | pubmed-10114999 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-101149992023-04-20 Berbamine suppresses intestinal SARS-CoV-2 infection via a BNIP3-dependent autophagy blockade Cloherty, Alexandra P. M. Rader, Anusca G. Patel, Kharishma S. Pérez-Vargas, Jimena Thompson, Connor A. H. Ennis, Siobhan Niikura, Masahiro Wildenberg, Manon E. Muncan, Vanesa Schreurs, Renée R. C. E. Jean, François Ribeiro, Carla M. S. Emerg Microbes Infect Coronaviruses SARS-CoV-2, the causative virus of COVID-19, continues to threaten global public health. COVID-19 is a multi-organ disease, causing not only respiratory distress, but also extrapulmonary manifestations, including gastrointestinal symptoms with SARS-CoV-2 RNA shedding in stool long after respiratory clearance. Despite global vaccination and existing antiviral treatments, variants of concern are still emerging and circulating. Of note, new Omicron BA.5 sublineages both increasingly evade neutralizing antibodies and demonstrate an increased preference for entry via the endocytic entry route. Alternative to direct-acting antivirals, host-directed therapies interfere with host mechanisms hijacked by viruses, and enhance cell-mediated resistance with a reduced likelihood of drug resistance development. Here, we demonstrate that the autophagy-blocking therapeutic berbamine dihydrochloride robustly prevents SARS-CoV-2 acquisition by human intestinal epithelial cells via an autophagy-mediated BNIP3 mechanism. Strikingly, berbamine dihydrochloride exhibited pan-antiviral activity against Omicron subvariants BA.2 and BA.5 at nanomolar potency, providing a proof of concept for the potential for targeting autophagy machinery to thwart infection of current circulating SARS-CoV-2 subvariants. Furthermore, we show that autophagy-blocking therapies limited virus-induced damage to intestinal barrier function, affirming the therapeutic relevance of autophagy manipulation to avert the intestinal permeability associated with acute COVID-19 and post-COVID-19 syndrome. Our findings underscore that SARS-CoV-2 exploits host autophagy machinery for intestinal dissemination and indicate that repurposed autophagy-based antivirals represent a pertinent therapeutic option to boost protection and ameliorate disease pathogenesis against current and future SARS-CoV-2 variants of concern. Taylor & Francis 2023-04-17 /pmc/articles/PMC10114999/ /pubmed/36951188 http://dx.doi.org/10.1080/22221751.2023.2195020 Text en © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group, on behalf of Shanghai Shangyixun Cultural Communication Co., Ltd https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. |
spellingShingle | Coronaviruses Cloherty, Alexandra P. M. Rader, Anusca G. Patel, Kharishma S. Pérez-Vargas, Jimena Thompson, Connor A. H. Ennis, Siobhan Niikura, Masahiro Wildenberg, Manon E. Muncan, Vanesa Schreurs, Renée R. C. E. Jean, François Ribeiro, Carla M. S. Berbamine suppresses intestinal SARS-CoV-2 infection via a BNIP3-dependent autophagy blockade |
title | Berbamine suppresses intestinal SARS-CoV-2 infection via a BNIP3-dependent autophagy blockade |
title_full | Berbamine suppresses intestinal SARS-CoV-2 infection via a BNIP3-dependent autophagy blockade |
title_fullStr | Berbamine suppresses intestinal SARS-CoV-2 infection via a BNIP3-dependent autophagy blockade |
title_full_unstemmed | Berbamine suppresses intestinal SARS-CoV-2 infection via a BNIP3-dependent autophagy blockade |
title_short | Berbamine suppresses intestinal SARS-CoV-2 infection via a BNIP3-dependent autophagy blockade |
title_sort | berbamine suppresses intestinal sars-cov-2 infection via a bnip3-dependent autophagy blockade |
topic | Coronaviruses |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10114999/ https://www.ncbi.nlm.nih.gov/pubmed/36951188 http://dx.doi.org/10.1080/22221751.2023.2195020 |
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