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

ABSTRACT: Coagulopathy 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.

SUBMITTER: Buonvino S

PROVIDER: S-EPMC7691694 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Buonvino Silvia S Melino Sonia S

Cell death discovery 20201127

Coagulopathy 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 ...[more]

PMID: 33262894

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Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic caused the biggest public health crises in recent history. Many expect future coronavirus introductions into the human population. Hence, it is essential to understand the basic biology of these viruses. In natural infection, the SARS-CoV-2 Spike (S) glycoprotein is co-expressed with all other viral proteins, which modify cellular compartments to maximize virion assembly. By comparison, most of S is degraded when the protein is expressed in isolation, as in current molecular vaccines. To probe the maturation pathway of S, we redirected its maturation by fusing S to the tetraspanin protein CD81. CD81 is a defining constituent of extracellular vesicles (EVs) or exosomes. EVs are generated in large numbers by all cells, extruded into blood and lymph, and transfer cargo between cells and systemically (estimated 1012 EVs per mL plasma). EVs, like platelets, can be transfused between unrelated donors. When fusing the proline-stabilized form of strain Delta S into the flexible, large extracellular loop of CD81 rather than being degraded in the lysosome, S was extruded into EVs. CD81-S fusion containing EVs were produced in large numbers and could be isolated to high purity. Purified CD81::S EVs bound ACE2, and S displayed on individual EV was observed by cryogenic electron microscopy (EM). The CD81::S-fusion EVs were non-toxic and elicited an anti-S trimer and anti-RBD antibody response in mice. This report shows a design path to maximize viral glycoprotein assembly and release without relying on the co-expression of potentially pathogenic nonstructural viral proteins.ImportanceThe severe acute respiratory syndrome coronavirus 2 pandemic caused the biggest public health crises in recent history. To understand the maturation pathway of S, we fused S to the tetraspanin protein CD81. The resulting molecule is secreted in extracellular vesicles and induces antibodies in mice. This may be a general design path for viral glycoprotein vaccines.

Project description:BackgroundThe 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.ResultsIn 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.ConclusionsThis 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.

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

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

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