The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens efforts to contain the coronavirus disease 2019 (COVID-19) pandemic. The number of COVID-19 cases and ...deaths in India has risen steeply, and a SARS-CoV-2 variant, B.1.617, is believed to be responsible for many of these cases. The spike protein of B.1.617 harbors two mutations in the receptor binding domain, which interacts with the angiotensin converting enzyme 2 (ACE2) receptor and constitutes the main target of neutralizing antibodies. Therefore, we analyze whether B.1.617 is more adept in entering cells and/or evades antibody responses. B.1.617 enters two of eight cell lines tested with roughly 50% increased efficiency and is equally inhibited by two entry inhibitors. In contrast, B.1.617 is resistant against bamlanivimab, an antibody used for COVID-19 treatment. B.1.617 evades antibodies induced by infection or vaccination, although less so than the B.1.351 variant. Collectively, our study reveals that antibody evasion of B.1.617 may contribute to the rapid spread of this variant.
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•B.1.617 spike mediates enhanced entry into Calu-3 and Caco-2 cells•Entry by the B.1.617 spike is blocked by soluble ACE2 and camostat•The therapeutic antibody bamlanivimab fails to neutralize the B.1.617 spike•B.1.617 spike evades neutralizing antibodies triggered by infection and vaccination
Between March and May 2021, India reported a steep increase in COVID-19 cases that was linked to SARS-CoV-2 variants, including B.1.617. Hoffmann et al. show that the B.1.617 spike protein mediates robust entry into human cells and evades neutralization by antibodies produced upon infection and vaccination.
Several SARS-CoV-2 variants emerged that harbor mutations in the surface unit of the viral spike (S) protein that enhance infectivity and transmissibility. Here, we analyzed whether ten ...naturally-occurring mutations found within the extended loop harboring the S1/S2 cleavage site of the S protein, a determinant of SARS-CoV-2 cell tropism and pathogenicity, impact S protein processing and function. None of the mutations increased but several decreased S protein cleavage at the S1/S2 site, including S686G and P681H, the latter of which is found in variants of concern B.1.1.7 (Alpha variant) and B.1.1.529 (Omicron variant). None of the mutations reduced ACE2 binding and cell-cell fusion although several modulated the efficiency of host cell entry. The effects of mutation S686G on viral entry were cell-type dependent and could be linked to the availability of cathepsin L for S protein activation. These results show that polymorphisms at the S1/S2 site can modulate S protein processing and host cell entry.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Small molecule inhibitors of pre-mRNA splicing are important tools for identifying new spliceosome assembly intermediates, allowing a finer dissection of spliceosome dynamics and function. Here, we ...identified a small molecule that inhibits human pre-mRNA splicing at an intermediate stage during conversion of pre-catalytic spliceosomal B complexes into activated B
complexes. Characterization of the stalled complexes (designated B
) revealed that U4/U6 snRNP proteins are released during activation before the U6 Lsm and B-specific proteins, and before recruitment and/or stable incorporation of Prp19/CDC5L complex and other B
complex proteins. The U2/U6 RNA network in B
complexes differs from that of the B
complex, consistent with the idea that the catalytic RNA core forms stepwise during the B to B
transition and is likely stabilized by the Prp19/CDC5L complex and related proteins. Taken together, our data provide new insights into the RNP rearrangements and extensive exchange of proteins that occurs during spliceosome activation.
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.
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.
The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) facilitates viral entry into host cells and is the key target for neutralizing antibodies. The SARS-CoV-2 lineage ...B.1.620 carries fifteen mutations in the S protein and is spread in Africa, the US and Europe, while lineage R.1 harbors four mutations in S and infections were observed in several countries, particularly Japan and the US. However, the impact of the mutations in B.1.620 and R.1 S proteins on antibody-mediated neutralization and host cell entry are largely unknown. Here, we report that these mutations are compatible with robust ACE2 binding and entry into cell lines, and they markedly reduce neutralization by vaccine-induced antibodies. Our results reveal evasion of neutralizing antibodies by B.1.620 and R.1, which might have contributed to the spread of these lineages.
The viral spike (S) protein is the key target of the neutralising antibody response, and the omicron variant harbours more than 35 mutations in the S protein, which allow highly efficient evasion ...from neutralising antibodies.1 In keeping with these findings, the omicron variant efficiently spreads in populations with a high percentage of convalescent or vaccinated individuals.2,3 The three main subvariants of the omicron variant are BA.1, BA.2, and BA.3. The omicron subvariants display remarkable differences regarding S protein mutations, particularly with respect to the N-terminal domain and the receptor-binding domain (appendix pp 2–3), which are known to harbour key epitopes of neutralising antibodies.5,6 Here, we compared BA.1, BA.2, and BA.3 for sensitivity to neutralisation by antibodies induced by infection and vaccination, using pseudoviruses as a model system, which adequately mirrors SARS-CoV-2 neutralisation by antibodies.7 We analysed particles harbouring the S protein of B.1—which is identical to the wildtype strain apart from the D614G mutation—and S proteins of BA.1, BA.2, and BA.3. ...neutralisation by antibodies induced in fully vaccinated (three vaccine doses) individuals with breakthrough infection during the fourth wave in Germany (October, 2021, to January, 2022, dominated by the delta variant) was most potent and neutralisation of particles bearing omicron S protein was 9–12-times less efficient than B.1pp (BA.1 p=0·0020; BA.2 p=0·0039; BA.3 p=0·0039; appendix pp 2–3).
The Omicron variant of SARS-CoV-2 evades antibody-mediated neutralization with unprecedented efficiency. At least three Omicron sublineages have been identified—BA.1, BA.2, and BA.3—and BA.2 exhibits ...increased transmissibility. However, it is currently unknown whether BA.2 differs from the other sublineages regarding cell entry and antibody-mediated inhibition. Here, we show that BA.1, BA.2, and BA.3 enter and fuse target cells with similar efficiency and in an ACE2-dependent manner. However, BA.2 was not efficiently neutralized by seven of eight antibodies used for COVID-19 therapy, including Sotrovimab, which robustly neutralized BA.1. In contrast, BA.2 and BA.3 (but not BA.1) were appreciably neutralized by Cilgavimab, which could constitute a treatment option. Finally, all sublineages were comparably and efficiently neutralized by antibodies induced by BNT162b2 booster vaccination after previous two-dose homologous or heterologous vaccination. Collectively, the Omicron sublineages show comparable cell entry and neutralization by vaccine-induced antibodies but differ in susceptibility to therapeutic antibodies.
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•SARS-CoV-2 Omicron BA.1, BA.2, and BA.3 harbor shared and unique spike protein mutations•BA.1, BA.2, and BA.3 enter and fuse target cells with similar efficiency•mRNA vaccine boosters comparably increase neutralization of BA.1, BA.2, and BA.3•BA.1, BA.2, and BA.3 differ regarding neutralization by therapeutic antibodies
The SARS-CoV-2 Omicron variant contains at least three main sublineages that harbor shared and unique spike protein mutations. Arora et al. show that sublineages BA.1, BA.2, and BA.3 enter cells with similar efficiency and are comparably neutralized by antibodies induced by BNT162b2 booster vaccination but differ regarding neutralization by therapeutic antibodies.
The Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), B.1.617.2, emerged in India and has spread to over 80 countries. B.1.617.2 replaced B.1.1.7 as the dominant virus in ...the United Kingdom, resulting in a steep increase in new infections, and a similar development is expected for other countries. Effective countermeasures require information on susceptibility of B.1.617.2 to control by antibodies elicited by vaccines and used for coronavirus disease 2019 (COVID-19) therapy. We show, using pseudotyping, that B.1.617.2 evades control by antibodies induced upon infection and BNT162b2 vaccination, although to a lesser extent as compared to B.1.351. We find that B.1.617.2 is resistant against bamlanivimab, a monoclonal antibody with emergency use authorization for COVID-19 therapy. Finally, we show increased Calu-3 lung cell entry and enhanced cell-to-cell fusion of B.1.617.2, which may contribute to augmented transmissibility and pathogenicity of this variant. These results identify B.1.617.2 as an immune evasion variant with increased capacity to enter and fuse lung cells.
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•B.1.617.2 spike mediates enhanced entry into Calu-3 and Caco-2 cells•B.1.617.2 spike fuses cells more efficiently than wild-type spike•B.1.617.2 spike is bamlanivimab resistant•B.1.617.2 spike evades neutralizing antibodies induced by infection or vaccination
The B.1.617.2 (Delta) variant challenges efforts to control the COVID-19 pandemic. Arora et al. provide evidence that B.1.617.2 may enter human lung cells and fuse neighboring cells more efficiently than the initially circulating virus. Further, the study suggests that B.1.617.2 may evade neutralization by antibodies elicited upon infection and vaccination.
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