期刊论文详细信息
mBio
Evidence for an ACE2-Independent Entry Pathway That Can Protect from Neutralization by an Antibody Used for COVID-19 Therapy
Martin S. Winkler1  Hans-Martin Jäck2  Sebastian Schulz2  Nadine Krüger3  Amy Kempf3  Inga Nehlmeier3  Anzhalika Sidarovich3  Markus Hoffmann3  Stefan Pöhlmann3  Prerna Arora3  Luise Graichen3  Christine Goffinet4  Daniela Niemeyer4  Christian Drosten4 
[1] Department of Anesthesiology, University of Göttingen Medical Center, and Georg-August University of Göttingen, Göttingen, Germany;Division of Molecular Immunology, Department of Internal Medicine 3, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany;Infection Biology Unit, German Primate Center, Göttingen, Germany;Institute of Virology, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany;
关键词: ACE2;    COVID-19;    antibody;    neutralization;    spike;   
DOI  :  10.1128/mbio.00364-22
来源: DOAJ
【 摘 要 】

ABSTRACT SARS-CoV-2 variants of concern (VOC) acquired mutations in the spike (S) protein, including E484K, that confer resistance to neutralizing antibodies. However, it is incompletely understood how these mutations impact viral entry into host cells. Here, we analyzed how mutations at position 484 that have been detected in COVID-19 patients impact cell entry and antibody-mediated neutralization. We report that mutation E484D markedly increased SARS-CoV-2 S-driven entry into the hepatoma cell line Huh-7 and the lung cell NCI-H1299 without augmenting ACE2 binding. Notably, mutation E484D largely rescued Huh-7 but not Vero cell entry from blockade by the neutralizing antibody Imdevimab and rendered Huh-7 cell entry ACE2-independent. These results suggest that the naturally occurring mutation E484D allows SARS-CoV-2 to employ an ACE2-independent mechanism for entry that is largely insensitive against Imdevimab, an antibody employed for COVID-19 therapy. IMPORTANCE The interaction of the SARS-CoV-2 spike protein (S) with the cellular receptor ACE2 is considered essential for infection and constitutes the key target for antibodies induced upon infection and vaccination. Here, using a surrogate system for viral entry, we provide evidence that a naturally occurring mutation can liberate SARS-CoV-2 from ACE2-dependence and that ACE2-independent entry may protect the virus from neutralization by an antibody used for COVID-19 therapy.

【 授权许可】

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