RRC ID |
82716
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Author |
Arora P, Zhang L, Nehlmeier I, Kempf A, Graichen L, Kreitz E, Sidarovich A, Rocha C, Gärtner S, Winkler M, Schulz S, Jäck H-M, Hoffmann M, Pöhlmann S.
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Title |
Host cell lectins ASGR1 and DC-SIGN jointly with TMEM106B confer ACE2 independence and imdevimab resistance to SARS-CoV-2 pseudovirus with spike mutation E484D.
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Journal |
J Virol
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Abstract |
The naturally occurring mutation E484D in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can render viral entry ACE2 independent and imdevimab resistant. Here, we investigated whether the cellular proteins ASGR1, DC-SIGN, and TMEM106B, which interact with the viral S protein, can contribute to these processes. Employing S protein-pseudotyped particles, we found that expression of ASGR1 or DC-SIGN jointly with TMEM106B allowed for robust entry of mutant E484D into otherwise non-susceptible cells, while this effect was not observed upon separate expression of the single proteins and upon infection with SARS-CoV-2 wild type (WT). Furthermore, expression of ASGR1 or DC-SIGN conferred ACE2 independence and imdevimab resistance to entry of mutant E484D but not WT, and entry under those conditions was dependent on endogenous TMEM106B. These results suggest that engagement of certain cellular lectins can direct SARS-CoV-2 mutant E484D to an ACE2-independent, TMEM106B-dependent entry pathway that is not inhibited by imdevimab.IMPORTANCEThe interaction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein with the ACE2 receptor determines the viral cell tropism and is the key target of the neutralizing antibody response. Here, we show that SARS-CoV-2 with a single, naturally occurring mutation in the spike protein, E484D, can use the cellular lectins ASGR1 and DC-SIGN in conjunction with TMEM106B for ACE2-independent entry and evasion of therapeutic antibodies. These results suggest that engagement of cellular lectins might modulate target cell choice of SARS-CoV-2 and might allow evasion of certain neutralizing antibodies.
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Pages |
e0123024
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Published |
2025-1-10
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DOI |
10.1128/jvi.01230-24
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PMID |
39791910
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Resource |
Human and Animal Cells |
Li-7(RCB1941) |