Abstract

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.

Details

Title
Berbamine suppresses intestinal SARS-CoV-2 infection via a BNIP3-dependent autophagy blockade
Author
Cloherty, Alexandra P M 1   VIAFID ORCID Logo  ; Rader, Anusca G 2   VIAFID ORCID Logo  ; Patel, Kharishma S 1 ; Pérez-Vargas, Jimena 3 ; Thompson, Connor A H 3 ; Ennis, Siobhan 4 ; Niikura, Masahiro 4 ; Wildenberg, Manon E 5 ; Muncan, Vanesa 5 ; Renée R C E Schreurs 2 ; François, Jean 3 ; Ribeiro, Carla M S 2   VIAFID ORCID Logo 

 Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands; Infectious Diseases & Inflammatory Diseases Programs, Amsterdam Institute for Infection & Immunity, Amsterdam, The Netherlands 
 Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands; Infectious Diseases & Inflammatory Diseases Programs, Amsterdam Institute for Infection & Immunity, Amsterdam, The Netherlands; Amsterdam Gastroenterology & Metabolism, University of Amsterdam, Amsterdam, The Netherlands 
 Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, Canada 
 Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada 
 Amsterdam Gastroenterology & Metabolism, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology and Metabolism, Tytgat institute for Intestinal and Liver research, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands 
Publication year
2023
Publication date
Dec 2023
Publisher
Taylor & Francis Ltd.
e-ISSN
22221751
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2867482526
Copyright
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group, on behalf of Shanghai Shangyixun Cultural Communication Co., Ltd. This work is licensed under the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.