scholarly journals Attenuated fusogenicity and pathogenicity of SARS-CoV-2 Omicron variant

2022 ◽  
Author(s):  
Kei Sato ◽  
Rigel Suzuki ◽  
Daichi Yamasoba ◽  
Izumi Kimura ◽  
Lei Wang ◽  
...  
Keyword(s):  
South Africa ◽  
Cell Culture ◽  
Severe Acute Respiratory Syndrome ◽  
Global Health ◽  
Cell Fusion ◽  
Statistical Modelling ◽  
Hamster Model ◽  
S Protein ◽  
The Uk ◽  
Cell Cell

Abstract The emergence of a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, Omicron, is the most urgent concern in the global health in December 2021. Our statistical modelling estimates that Omicron is >3.0-fold and >5.6-fold more transmissible than Delta in South Africa and the UK, respectively. Intriguingly, cell culture experiments show that Omicron is less fusogenic than Delta and ancestral SARS-CoV-2. Although the spike (S) protein of Delta is efficiently cleaved into the two subunits, which facilitates cell-cell fusion, Omicron S is faintly cleaved. Further, in hamster model, Omicron shows decreased lung infectivity and is less pathogenic compared to Delta and ancestral SARS-CoV-2. Our data suggest that the efficacy of SARS-CoV-2 S cleavage and viral fusogenicity are closely associated with viral pathogenicity, and Omicron evolved to exhibit increased transmissibility and attenuated pathogenicity.

scholarly journals Design of Potent Membrane Fusion Inhibitors against SARS-CoV-2, an Emerging Coronavirus with High Fusogenic Activity

2020 ◽  
Vol 94 (14) ◽  
Author(s):  
Yuanmei Zhu ◽  
Danwei Yu ◽  
Hongxia Yan ◽  
Huihui Chong ◽  
Yuxian He
Keyword(s):  
Public Health ◽  
Severe Acute Respiratory Syndrome ◽  
Fusion Protein ◽  
Membrane Fusion ◽  
Cell Fusion ◽  
Heptad Repeat ◽  
Global Public Health ◽  
S Protein ◽  
Fusion Inhibitors ◽  
Cell Cell

ABSTRACT The 2019 coronavirus disease (COVID-19), caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed serious threats to global public health and economic and social stabilities, calling for the prompt development of therapeutics and prophylactics. In this study, we first verified that SARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) as a cell receptor and that its spike (S) protein mediates high membrane fusion activity. The heptad repeat 1 (HR1) sequence in the S2 fusion protein of SARS-CoV-2 possesses markedly increased α-helicity and thermostability, as well as a higher binding affinity with its corresponding heptad repeat 2 (HR2) site, than the HR1 sequence in S2 of severe acute respiratory syndrome coronavirus (SARS-CoV). Then, we designed an HR2 sequence-based lipopeptide fusion inhibitor, termed IPB02, which showed highly potent activities in inhibiting SARS-CoV-2 S protein-mediated cell-cell fusion and pseudovirus transduction. IPB02 also inhibited the SARS-CoV pseudovirus efficiently. Moreover, the structure-activity relationship (SAR) of IPB02 was characterized with a panel of truncated lipopeptides, revealing the amino acid motifs critical for its binding and antiviral capacities. Therefore, the results presented here provide important information for understanding the entry pathway of SARS-CoV-2 and the design of antivirals that target the membrane fusion step. IMPORTANCE The COVID-19 pandemic, caused by SARS-CoV-2, presents a serious global public health emergency in urgent need of prophylactic and therapeutic interventions. The S protein of coronaviruses mediates viral receptor binding and membrane fusion, thus being considered a critical target for antivirals. Herein, we report that the SARS-CoV-2 S protein has evolved a high level of activity to mediate cell-cell fusion, significantly differing from the S protein of SARS-CoV that emerged previously. The HR1 sequence in the fusion protein of SARS-CoV-2 adopts a much higher helical stability than the HR1 sequence in the fusion protein of SARS-CoV and can interact with the HR2 site to form a six-helical bundle structure more efficiently, underlying the mechanism of the enhanced fusion capacity. Also, importantly, the design of membrane fusion inhibitors with high potencies against both SARS-CoV-2 and SARS-CoV has provided potential arsenals to combat the pandemic and tools to exploit the fusion mechanism.

scholarly journals Naturally-acquired immunity in Syrian Golden Hamsters provides protection from re-exposure to emerging heterosubtypic SARS-CoV-2 variants B.1.1.7 and B.1.351

2021 ◽  
Author(s):  
Jordan J. Clark ◽  
Parul Sharma ◽  
Eleanor G. Bentley ◽  
Adam C. Harding ◽  
Anja Kipar ◽  
...  
Keyword(s):  
South Africa ◽  
Immune Responses ◽  
Clinical Signs ◽  
Acquired Immunity ◽  
Hamster Model ◽  
Syrian Golden Hamsters ◽  
Subsequent Exposure ◽  
Acquired Immune Responses ◽  
The Uk ◽  
Prior Infection

AbstractThe ability of acquired immune responses against SARS-CoV-2 to protect after subsequent exposure to emerging variants of concern (VOC) such as B1.1.7 and B1.351 is currently of high significance. Here, we use a hamster model of COVID-19 to show that prior infection with a strain representative of the original circulating lineage B of SARS-CoV-2 induces protection from clinical signs upon subsequent challenge with either B1.1.7 or B1.351 viruses, which recently emerged in the UK and South Africa, respectively. The results indicate that these emergent VOC may be unlikely to cause disease in individuals that are already immune due to prior infection, and this has positive implications for overall levels of infection and COVID-19 disease.

scholarly journals Important Role for the Transmembrane Domain of Severe Acute Respiratory Syndrome Coronavirus Spike Protein during Entry

2006 ◽  
Vol 80 (3) ◽  
pp. 1302-1310 ◽  
Author(s):  
Rene Broer ◽  
Bertrand Boson ◽  
Willy Spaan ◽  
François-Loïc Cosset ◽  
Jeroen Corver
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Membrane Fusion ◽  
Cell Fusion ◽  
Transmembrane Domain ◽  
Cytoplasmic Tail ◽  
Transmembrane Domains ◽  
Spike Protein ◽  
Fusion Activity ◽  
Wild Type ◽  
Cell Cell

ABSTRACT The spike protein (S) of severe acute respiratory syndrome coronavirus (SARS-CoV) is responsible for receptor binding and membrane fusion. It contains a highly conserved transmembrane domain that consists of three parts: an N-terminal tryptophan-rich domain, a central domain, and a cysteine-rich C-terminal domain. The cytoplasmic tail of S has previously been shown to be required for assembly. Here, the roles of the transmembrane and cytoplasmic domains of S in the infectivity and membrane fusion activity of SARS-CoV have been studied. SARS-CoV S-pseudotyped retrovirus (SARSpp) was used to measure S-mediated infectivity. In addition, the cell-cell fusion activity of S was monitored by a Renilla luciferase-based cell-cell fusion assay. Svsv-cyt, an S chimera with a cytoplasmic tail derived from vesicular stomatitis virus G protein (VSV-G), and Smhv-tmdcyt, an S chimera with the cytoplasmic and transmembrane domains of mouse hepatitis virus, displayed wild-type-like activity in both assays. Svsv-tmdcyt, a chimera with the cytoplasmic and transmembrane domains of VSV-G, was impaired in the SARSpp and cell-cell fusion assays, showing 3 to 25% activity compared to the wild type, depending on the assay and the cells used. Examination of the oligomeric state of the chimeric S proteins in SARSpp revealed that Svsv-tmdcyt trimers were less stable than wild-type S trimers, possibly explaining the lowered fusogenicity and infectivity.

scholarly journals Deletion of ER-retention motif on SARS-CoV-2 spike protein reduces cell hybrid during cell–cell fusion

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xuening Wang ◽  
Chih-Hsiung Chen ◽  
Saiaditya Badeti ◽  
Jong Hyun Cho ◽  
Alireza Naghizadeh ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Cell Lines ◽  
Cell Hybrid ◽  
Host Cells ◽  
Spike Protein ◽  
Expression Vectors ◽  
S Protein ◽  
Er Retention ◽  
Syncytia Formation ◽  
Cell Cell

Abstract Background The novel SARS-CoV-2 has quickly become a global pandemic since the first reported case in December 2019, with the virus infecting millions of people to date. The spike (S) protein of the SARS-CoV-2 virus plays a key role in binding to angiotensin-converting enzyme 2 (ACE2), a host cell receptor for SARS-CoV-2. S proteins that are expressed on the cell membrane can initiate receptor-dependent syncytia formation that is associated with extensive tissue damage. Formation of syncytia have been previously observed in cells infected with various other viruses (e.g., HIV, Ebola, Influenza, and Herpesviruses). However, this phenomenon is not well documented and the mechanisms regulating the formation of the syncytia by SARS-CoV-2 are not fully understood. Results In this study, we investigated the possibility that cell fusion events mediated by the S protein of SARS-CoV-2 and ACE2 interaction can occur in different human cell lines that mimic different tissue origins. These cell lines were transduced with either wild-type (WT-S) S protein or a mutated variant where the ER-retention motif was removed (Δ19-S), as well as human ACE2 expression vectors. Different co-culture combinations of spike-expressing 293T, A549, K562, and SK-Hep1 cells with hACE2-expressing cells revealed cell hybrid fusion. However, only certain cells expressing S protein can form syncytial structures as this phenomenon cannot be observed in all co-culture combinations. Thus, SARS-CoV-2 mediated cell–cell fusion represents a cell type-dependent process which might rely on a different set of parameters. Recently, the Δ19-S variant is being widely used to increase SARS-CoV-2 pseudovirus production for in vitro assays. Comparison of cell fusion occurring via Δ19-S expressing cells shows defective nuclear fusion and syncytia formation compared to WT-S. Conclusions This distinction between the Δ19-S variant and WT-S protein may have downstream implications for studies that utilize pseudovirus-based entry assays. Additionally, this study suggest that spike protein expressed by vaccines may affect different ACE2-expressing host cells after SARS-CoV-2 vaccine administration. The long-term effects of these vaccines should be monitored carefully. Δ19-S mRNA may represent a safer mRNA vaccine design in the future.

scholarly journals New Consensus pattern in Spike CoV-2: potential implications in coagulation process and cell–cell fusion

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Silvia Buonvino ◽  
Sonia Melino
Keyword(s):  
Cell Fate ◽  
Cell Fusion ◽  
Molecular Mechanisms ◽  
Coagulation Factor ◽  
Cell Interaction ◽  
Factor X ◽  
S Protein ◽  
Coagulation Process ◽  
Consensus Pattern ◽  
Cell Cell

AbstractCoagulopathy and syncytial formation are relevant effects of the SARS-CoV-2 infection, but the underlying molecular mechanisms triggering these processes are not fully elucidated. Here, we identified a potential consensus pattern in the Spike S glycoprotein present within the cytoplasmic domain; this consensus pattern was detected in only 79 out of 561,000 proteins (UniProt bank). Interestingly, the pattern was present in both human and bat the coronaviruses S proteins, in many proteins involved in coagulation process, cell–cell interaction, protein aggregation and regulation of cell fate, such as von Willebrand factor, coagulation factor X, fibronectin and Notch, characterized by the presence of the cysteine-rich EGF-like domain. This finding may suggest functional similarities between the matched proteins and the CoV-2 S protein, implying a new possible involvement of the S protein in the molecular mechanism that leads to the coagulopathy and cell fusion in COVID-19 disease.

scholarly journals A bivalent protein targeting glycans and HR1 domain in spike protein potently inhibited infection of SARS-CoV-2 and other human coronaviruses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yanxing Cai ◽  
Wei Xu ◽  
Jiayi Tang ◽  
Najing Cao ◽  
Qiaoshuai Lan ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Mechanism Of Action ◽  
Broad Spectrum ◽  
Inhibitory Activity ◽  
Inhibitory Peptide ◽  
Newborn Mice ◽  
S Protein ◽  
Human Coronaviruses ◽  
Potent Inhibitory Activity ◽  
Cell Cell

Abstract Background Our previous studies have shown that combining the antiviral lectin GRFT and the pan-CoV fusion inhibitory peptide EK1 results in highly potent inhibitory activity against SARS-CoV-2 infection. In this study, we aimed to design and construct a bivalent protein consisting of GRFT and EK1 components and evaluate its inhibitory activity and mechanism of action against infection by SARS-CoV-2 and its mutants, as well as other human coronaviruses (HCoVs). Methods The bivalent proteins were expressed in E. coli and purified with Ni-NTA column. HIV backbone-based pseudovirus (PsV) infection and HCoV S-mediated cell–cell fusion assays were performed to test their inhibitory activity. ELISA and Native-PAGE were conducted to illustrate the mechanism of action of these bivalent proteins. Five-day-old newborn mice were intranasally administrated with a selected bivalent protein before or after HCoV-OC43 challenge, and its protective effect was monitored for 14 days. Results Among the three bivalent proteins purified, GL25E exhibited the most potent inhibitory activity against infection of SARS-CoV-2 PsVs expressing wild-type and mutated S protein. GL25E was significantly more effective than GRFT and EK1 alone in inhibiting HCoV S-mediated cell–cell fusion, as well as infection by SARS-CoV-2 and other HCoVs, including SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63 and HCoV-OC43. GL25E could inhibit authentic SASR-CoV-2, HCoV-OC43 and HCoV-229E infection in vitro and prevent newborn mice from authentic HCoV-OC43 infection in vivo. GL25E could bind to glycans in the S1 subunit and HR1 in the S2 subunit in S protein, showing a mechanism of action similar to that of GRFT and EK1 alone. Conclusions Since GL25E showed highly potent and broad-spectrum inhibitory activity against infection of SARS-CoV-2 and its mutants, as well as other HCoVs, it is a promising candidate for further development as a broad-spectrum anti-HCoV therapeutic and prophylactic to treat and prevent COVID-19 and other emerging HCoV diseases.

scholarly journals Deletion of ER-retention Motif on SARS-CoV-2 Spike Protein Reduces Cell Hybrid During Cell-cell Fusion

2021 ◽  
Author(s):  
Chih-Hsiung Chen ◽  
Saiaditya Badeti ◽  
Jong Hyun Cho ◽  
Alireza Naghizadeh ◽  
Xuening Wang ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Cell Lines ◽  
Cell Hybrid ◽  
Host Cells ◽  
Spike Protein ◽  
In Vitro Assays ◽  
S Protein ◽  
Er Retention ◽  
Syncytia Formation ◽  
Cell Cell

Abstract The novel SARS-CoV-2 has quickly become a global pandemic since the first reported case in December 2019, with the virus infecting millions of people to date. The spike (S) protein of the SARS-CoV-2 virus plays a key role in binding to angiotensin-converting enzyme 2 (ACE2), a host cell receptor for SARS-CoV-2. S proteins that are expressed on the cell membrane can initiate receptor-dependent syncytia formation that is associated with extensive tissue damage. Formation of syncytia have been previously observed in cells infected with various other viruses (e.g., HIV, Ebola, Influenza, and Herpesviruses). However, this phenomenon is not well documented and the mechanisms regulating the formation of these syncytia by SARS-CoV-2 are not fully understood. In this study, we investigated the possibility that cell fusion events mediated by the S protein of SARS-CoV-2 and ACE2 interaction can occur in different human cell lines that mimic different tissue origins. These cell lines were stably transduced with either wild-type (WT-S) S protein or a mutated variant where the ER-retention motif was removed (Δ19-S), or human ACE2 vectors. Different co-culture combinations of spike-expressing 293T, A549, K562, and SK-Hep1 cells with hACE2-expressing cells revealed cell hybrid fusion. However, only certain cells expressing S protein can form syncytial structures as this phenomenon cannot be observed in all co-culture combinations. Thus, SARS-CoV-2 mediated cell-cell fusion represents a cell type-dependent process which might rely on a different set of parameters. Recently, the Δ19-S variant is being widely used to increase SARS-CoV-2 pseudovirus production for in vitro assays. Comparison of cell fusion occurring via Δ19-S expressing cells shows defective nuclear fusion and syncytia formation compared to WT-S. This distinction between the Δ19-S variant and WT-S protein may have downstream implications for studies that utilize pseudovirus-based entry assays. Additionally, this study suggest that spike protein expressed by vaccines may affect different ACE2-expressing host cells after SARS-CoV-2 vaccine administration. The long-term effects of these vaccines should be monitored carefully.

scholarly journals Neutralizing response against E484K variant after original SARS-CoV-2 infection

2021 ◽  
Author(s):  
Takuma Hayashi ◽  
Nobuo Yaegashi ◽  
Ikuo Konishi
Keyword(s):  
South Africa ◽  
United Kingdom ◽  
Severe Acute Respiratory Syndrome ◽  
The Body ◽  
Proliferative Potential ◽  
Spike Glycoprotein ◽  
Highly Pathogenic ◽  
The United Kingdom ◽  
The Uk ◽  
Neutralization Response

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) variants, which are spreading in the United Kingdom (UK) and elsewhere, have been found in infected individuals in Japan. The virus mutates, to facilitate its life in the host, during the process of repeated proliferation in the body of the host, including humans. In other words, it is natural that a human-compatible mutant strain always predominates in infection and proliferation. As a result, the viral mutants acquire strong proliferative potential in the host and are highly pathogenic. The number of people infected with the mutated SARS-CoV-2 variant E484K, which is different from the SARS-CoV-2 variants that are spreading in the UK, South Africa, and Brazil, is increasing in Tokyo. It has been pointed out that the effects of immunity and vaccines may be reduced against the Tokyo-type SARS-CoV-2 variant E484K. We have investigated the neutralization response to various mutations in the spike glycoprotein using the serum of people already infected with the original SARS-CoV-2. The results showed that SARS-CoV-2 variants with Y543F or N501Y mutations in the spike glycoprotein affect the neutralization reaction. However, single E484K mutations within the spiked glycoprotein of the Tokyo-type SARS-CoV-2 variant are unlikely to have a significant effect on the affinity of the host antibody for the virus.

scholarly journals Mild Symptomatic SARS-CoV-2 P.1 (B.1.1.28) Infection in a Fully Vaccinated 83-Year-Old Man

Pathogens ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 614
Author(s):  
Marco Fabiani ◽  
Katia Margiotti ◽  
Antonella Viola ◽  
Alvaro Mesoraca ◽  
Claudio Giorlandino
Keyword(s):  
South Africa ◽  
Severe Acute Respiratory Syndrome ◽  
Vaccine Efficacy ◽  
Therapeutic Antibody ◽  
The Novel ◽  
The World ◽  
The Uk

The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) and the associated coronavirus disease 2019 (COVID-19) continue to spread throughout the world, causing more than 120 million infections. Several variants of concern (VOCs) have emerged and spread with implications for vaccine efficacy, therapeutic antibody treatments, and possible reinfections. On 17 March 2021, several VOCs were detected, including lineage B.1.1.7, first identified in the UK, B.1.351 in South Africa, Lineage P.1 (B.1.1.28.1) in Brazil, and novel Sub-Lineage A (A.23.1), reported in Uganda, and B.1.525, reported in Nigeria. Here, we describe an 83-year-old man infected with the SARS-CoV-2 P.1 variant after two doses of the BNT162b2 mRNA COVID-19 vaccine.

Sign in / Sign up

Export Citation Format

Share Document