Lectins enhance SARS-CoV-2 infection and influence neutralizing antibodies

Lempp, Florian A.; Soriaga, Leah; Montiel-Ruiz, Martin; Benigni, Fabio; Noack, Julia; Park, Young-Jun; Bianchi, Siro; Walls, Alexandra C.; Bowen, John E.; Zhou, Jiayi; Kaiser, Hannah; Joshi, Anshu; Agostini, Marco; Meury, Marcel; Dellota, Exequiel; Jaconi, Stefano; Cameroni, Elisabetta; Martínez-Picado, Javier; Vergara‐Alert, Júlia; Izquierdo-Useros, Nuria; Virgin, Herbert W.; Lanzavecchia, Antonio; Veesler, David; Purcell, Lisa A.; Telenti, Amalio; Corti, Davide

doi:10.1038/s41586-021-03925-1

Cited by 282 publications

(344 citation statements)

References 69 publications

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“…S2K146 induced shedding of the S1 subunit as efficiently as the RBM-targeting S2E12 mAb, whereas the control mAb S2M11 did not as it locks S in the prefusion closed state (13) (Fig 4C). Furthermore, we found that the S2K146 Fab triggered the fusogenic rearrangement of a wildtype-like S ectodomain trimer, as we previously described for several SARS-CoV and SARS-CoV-2 neutralizing mAbs (14,(31)(32)(33) (Fig 4D). These data show that S2K146-mediated sarbecovirus neutralization relies on competitively blocking viral attachment to the ACE2 receptor and inactivation of S trimers at the surface of virions before encountering host cells.…”

Section: S2k146 Inhibits Ace2 Engagement and Protects Hamsters From Sars-cov-2 Challengesupporting

confidence: 84%

“…The SARS-CoV-2 S 'wildtype' ectodomain trimer used for refolding experiments followed by negative stain EM was engineered as follows and recombinantly expressed as previously described (32). The SARS-CoV-2 S D614G 'wildtype' has a muphosphatase signal peptide ending in ETGT, begins at Q14, a mutated S1/S2 cleavage site (SGAR), ends at residue K1211 and is followed by a TEV cleavage site, fold-on trimerization motif, and an 8× His tag in the pCMV vector.…”

Section: Recombinant Protein Productionmentioning

confidence: 99%

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Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry

Park

Marco

Starr

et al. 2021

Preprint

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Understanding broadly neutralizing sarbecovirus antibody responses is key to developing countermeasures effective against SARS-CoV-2 variants and future spillovers of other sarbecoviruses. Here we describe the isolation and characterization of a human monoclonal antibody, designated S2K146, broadly neutralizing viruses belonging to all three sarbecovirus clades known to utilize ACE2 as entry receptor and protecting therapeutically against SARS-CoV-2 beta challenge in hamsters. Structural and functional studies show that most of the S2K146 epitope residues are shared with the ACE2 binding site and that the antibody inhibits receptor attachment competitively. Viral passaging experiments underscore an unusually high barrier for emergence of escape mutants making it an ideal candidate for clinical development. These findings unveil a key site of vulnerability for the development of a next generation of vaccines eliciting broad sarbecovirus immunity.

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Section: S2k146 Inhibits Ace2 Engagement and Protects Hamsters From Sars-cov-2 Challengesupporting

confidence: 84%

Section: Recombinant Protein Productionmentioning

confidence: 99%

Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry

Park

Marco

Starr

et al. 2021

Preprint

Self Cite

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“…Our deep mutational scanning measured binding to yeast-displayed RBD, which may not capture all relevant features of full-length spike in the context of virus. Finally, our neutralization assays used pseudotyped lentiviral particles and ACE2-overexpressing cells, and some recent works suggest that the relative importance of different spike epitopes for neutralization can depend on the viral system and target cell line used (7,35,36,60).…”

Section: Discussionmentioning

confidence: 99%

“…2C). One caveat is that all neutralization assays were performed in 293T cells overexpressing ACE2, which tend to emphasize the effect of RBD-binding, ACE2-competitive antibodies more than assays performed on cells with lower levels of ACE2 expression (7,35,36).…”

Section: Infection With B1351 Elicits a Neutralizing Antibody Response At Least As Rbd-focused As Early 2020 Virusesmentioning

confidence: 99%

A SARS-CoV-2 variant elicits an antibody response with a shifted immunodominance hierarchy

Greaney

Starr

Eguia

et al. 2021

Preprint

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Many SARS-CoV-2 variants have mutations at key sites targeted by antibodies. However, it is unknown if antibodies elicited by infection with these variants target the same or different regions of the viral spike as antibodies elicited by earlier viral isolates. Here we compare the specificities of polyclonal antibodies produced by humans infected with early 2020 isolates versus the B.1.351 variant of concern (also known as Beta or 20H/501Y.V2), which contains mutations in multiple key spike epitopes. The serum neutralizing activity of antibodies elicited by infection with both early 2020 viruses and B.1.351 is heavily focused on the spike receptor-binding domain (RBD). However, within the RBD, B.1.351-elicited antibodies are more focused on the "class 3" epitope spanning sites 443 to 452, and neutralization by these antibodies is notably less affected by mutations at residue 484. Our results show that SARS-CoV-2 variants can elicit polyclonal antibodies with different immunodominance hierarchies.

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“…Interestingly, cholesterol-bound RNA probes are targeted to mitochondria 60 . Furthermore, several alternative entry factors to ACE2 and facilitators capable to mediate SARS-CoV-2 infection have been identified [61][62][63][64] , and they could mediate SARS-CoV-2 caveolae-mediated endocytosis. Taken together, it is possible that the diversity of receptors and entry pathways exploited by SARS-CoV-2, together with the fast dynamics of PM-mitochondria communication can obscure the caveolae role.…”

Section: Mitochondria Infection By Vrnamentioning

confidence: 99%

Evidence of mitochondria origin of SARS-CoV-2 double-membrane vesicles: a review.

Oca-B

2021

F1000Res

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Coronavirus Disease-19 (COVID-19) pandemic is caused by the coronavirus SARS-CoV-2 that has infected in a year more than 200 million people and has killed almost 4.5 million people worldwide. This infection affects mainly certain groups of people that have high susceptibility to present severe COVID-19 due to comorbidities. Moreover, the long-COVID-19 comprises a series of symptoms that may remain in some patients for months after infection that further compromises health of individuals. Therefore, this pandemic poses a serious emergency worldwide. Thus, since this pandemic is profoundly affecting economic and social life of societies, a deeper understanding of SARS-CoV-2 infection cycle could help to envisage novel therapeutic alternatives that limit or stop COVID-19. Several recent findings have unexpectedly found that mitochondria play a critical role in SARS-CoV-2 cell infection. Indeed, it has been suggested that this organelle could be the origin of its replication niches, the double membrane vesicles (DMV), as its been observed with another virus. In this regard, mitochondria derived vesicles (MDV), involved in mitochondria quality control, were discovered more than 10 years ago and interestingly there is a population characterized by a double membrane. MDV shedding is induced by mitochondrial stress and it has a fast assembly dynamic, reason that perhaps has precluded their identification in electron microscopy or tomography studies. These and other features of MDV together with recent SARS-CoV-2 protein interactome with the host and other findings linking SARS-CoV-2 to mitochondria, support that these vesicles are the precursors of SARS-CoV-2 induced DMV. In this work, the celular, molecular, phenotypical and biochemical evidence that supports this hypothesis is reviewed and integrated into the current model of SARS-CoV-2 cell infection. In this scheme, some relevant questions are raised as pending topics for research that would help in the near future to test this hypothesis. The intention (abstract truncated).

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Lectins enhance SARS-CoV-2 infection and influence neutralizing antibodies

Cited by 282 publications

References 69 publications

Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry

Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry

A SARS-CoV-2 variant elicits an antibody response with a shifted immunodominance hierarchy

Evidence of mitochondria origin of SARS-CoV-2 double-membrane vesicles: a review.

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