https://orcid.org/0000-0002-9850-9643
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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.
Acknowledgements
We would like to acknowledge Dr. Andrea Olmstead for her helpful contributions to the initial discussions regarding studies performed with Omicron BA.2 and BA.5 and Dr. Athanasios Koulis for assisting in human intestinal organoid culture. HIS mouse facility (Amsterdam UMC, The Netherlands) is acknowledged for providing fetal tissues. The authors would like to thank Dr. Kees Weijer, Mrs. Esther Siteur-van Rijnstra, Mrs. Cynthia A van der Linden, and Dr. Arie Voordouw for facilitating the provision of the fetal material. We thank the Cellular Imaging Core Facility of the Amsterdam UMC for technical assistance during flow cytometric and advanced light microscopy data acquisition. The authors acknowledge the support of the CL3 facility (Facility for Infectious Disease and Epidemic Research [FINDER]) of the Life Sciences Institute of the University of British Columbia founded by Dr. François Jean. We further thank Dr. Alex Ball, Jr., MD, Senior Scientist (Genetex), for supplying the SARS-CoV-2 (COVID-19) nucleocapsid antibody [HL344] (GTX635679), and Dr. Neeltje A. Kootstra (Department of Experimental Immunology, Amsterdam UMC) for sharing the backbone plasmid used for the production of pseudotyped SARS-CoV-2 virus within this work. Finally, we also acknowledge a generous donation towards the purchase of the CellInsight CX7 HCS system provided by the Vancouver General Hospital Foundation to Dr. Jean. Graphical illustrations were made using BioRender (https://biorender.com).
Disclosure statement
No potential conflict of interest was reported by the author(s).