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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.
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1 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
2 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
3 Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, Canada
4 Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada
5 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