Increased lung cell entry of B.1.617.2 and evasion of antibodies induced by infection and BNT162b2 vaccination

Arora, Prerna; Krueger, Nadine; Kempf, Amy; Nehlmeier, Inga; Sidarovich, Anzhalika; Graichen, Luise; Moldenhauer, Anna-Sophie; Winkler, Martin Sebastian; Schulz, Sebastian; Jaeck, Hans-Martin; Stankov, Metodi V.; Behrens, Georg M. N.; Poehlmann, Stefan; Hoffmann, Markus

doi:10.1101/2021.06.23.449568

Cited by 18 publications

(18 citation statements)

References 37 publications

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“…In another recent study, it has been reported that infection with B.1.617.2 variant could be controlled by antibodies induced due to prior infection or BNT162b2 vaccination, but with lower efficacy than the B.1.351 variant. This study further demonstrated that B.1.617.2 variant has greater lung cell entry and cell to cell fusion, indicating its higher lung infection capacity [30]. Although various studies have shown the phenotypic effect of the mutations, and increased transmissibility, limited data exist on comparative dynamics, molecular interactions, and changes in energetics due to these crucial mutations in the RBD domain of the spike protein of various mutants.…”

Section: Introductionmentioning

confidence: 51%

Possible Link between Higher Transmissibility of Alpha, Kappa and Delta Variants of SARS-CoV-2 and Increased Structural Stability of Its Spike Protein and hACE2 Affinity

Kumar

Singh

Hasnain

et al. 2021

IJMS

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The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) outbreak in December 2019 has caused a global pandemic. The rapid mutation rate in the virus has created alarming situations worldwide and is being attributed to the false negativity in RT-PCR tests. It has also increased the chances of reinfection and immune escape. Recently various lineages namely, B.1.1.7 (Alpha), B.1.617.1 (Kappa), B.1.617.2 (Delta) and B.1.617.3 have caused rapid infection around the globe. To understand the biophysical perspective, we have performed molecular dynamic simulations of four different spikes (receptor binding domain)-hACE2 complexes, namely wildtype (WT), Alpha variant (N501Y spike mutant), Kappa (L452R, E484Q) and Delta (L452R, T478K), and compared their dynamics, binding energy and molecular interactions. Our results show that mutation has caused significant increase in the binding energy between the spike and hACE2 in Alpha and Kappa variants. In the case of Kappa and Delta variants, the mutations at L452R, T478K and E484Q increased the stability and intra-chain interactions in the spike protein, which may change the interaction ability of neutralizing antibodies to these spike variants. Further, we found that the Alpha variant had increased hydrogen interaction with Lys353 of hACE2 and more binding affinity in comparison to WT. The current study provides the biophysical basis for understanding the molecular mechanism and rationale behind the increase in the transmissivity and infectivity of the mutants compared to wild-type SARS-CoV-2.

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Section: Introductionmentioning

confidence: 51%

Possible Link between Higher Transmissibility of Alpha, Kappa and Delta Variants of SARS-CoV-2 and Increased Structural Stability of Its Spike Protein and hACE2 Affinity

Kumar

Singh

Hasnain

et al. 2021

IJMS

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“…In their very recent study, Arora et al explored the internalization efficacy of the Delta spike variant on various cell lines [ 15 ]. In those studies, Caco-2 and Calu-3 cells, compared to 293T, exhibited a markedly increased cellular uptake of the Delta spike variant.…”

Section: Resultsmentioning

confidence: 99%

“…The Delta’s mutations result in multiple replacements of neutral or negatively charged amino acids with positively charged ones [ 13 ]. On the other hand, the spike protein’s shift towards a positive electrostatic potential does not lead to increased affinity towards ACE2, a cell surface protease widely recognized as the main cell entry receptor for SARS-CoV-2 [ 14 , 15 , 16 , 17 ]. A recent study showed that mutating the intracellular domain of ACE2 does not affect the intracellular entry of SARS-CoV-2, suggesting that the internalization of the virus is driven by ACE2 independent receptors [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission

Hudák¹,

Veres²,

Letoha

et al. 2022

IJMS

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Emerging SARS-CoV-2 variants pose threats to vaccination campaigns against COVID-19. Being more transmissible than the original virus, the SARS-CoV-2 B.1.617 lineage, named the Delta variant, swept through the world in 2021. The mutations in the Delta’s spike protein shift the protein towards a net positive electrostatic potential. To understand the key molecular drivers of the Delta infection, we investigate the cellular uptake of the Delta spike protein and Delta spike-bearing SARS-CoV-2 pseudoviruses. Specific in vitro modification of ACE2 and syndecan expression enabled us to demonstrate that syndecan-4, the syndecan isoform abundant in the lung, enhances the transmission of the Delta variant by attaching its mutated spike glycoprotein and facilitating its cellular entry. Compared to the wild-type spike, the Delta one shows a higher affinity towards heparan sulfate proteoglycans than towards ACE2. In addition to attachment to the polyanionic heparan sulfate chains, the Delta spike’s molecular interactions with syndecan-4 also involve syndecan-4’s cell-binding domain that mediates cell-to-cell adhesion. Regardless of the complexity of these interactions, exogenously added heparin blocks Delta’s cellular entry as efficiently as syndecan-4 knockdown. Therefore, a profound understanding of the molecular mechanisms underlying Delta infections enables the development of molecularly targeted yet simple strategies to reduce the Delta variant’s spread.

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“…We used a vesicular stomatitis virus-based pseudotyped virus assay to analyse neutralisation. 6 This study was approved by the Internal Review Board of Hannover Medical School. All participants gave written informed consent.…”

Section: Sars-cov-2 Delta Variant Neutralisation After Heterologous Chadox1-s/bnt162b2 Vaccinationmentioning

confidence: 99%

SARS-CoV-2 delta variant neutralisation after heterologous ChAdOx1-S/BNT162b2 vaccination

et al. 2021

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Increased lung cell entry of B.1.617.2 and evasion of antibodies induced by infection and BNT162b2 vaccination

Cited by 18 publications

References 37 publications

Possible Link between Higher Transmissibility of Alpha, Kappa and Delta Variants of SARS-CoV-2 and Increased Structural Stability of Its Spike Protein and hACE2 Affinity

Possible Link between Higher Transmissibility of Alpha, Kappa and Delta Variants of SARS-CoV-2 and Increased Structural Stability of Its Spike Protein and hACE2 Affinity

Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission

SARS-CoV-2 delta variant neutralisation after heterologous ChAdOx1-S/BNT162b2 vaccination

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