4.7 Article

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

Journal

CELL AND BIOSCIENCE
Volume 11, Issue 1, Pages -

Publisher

BMC
DOI: 10.1186/s13578-021-00626-0

Keywords

SARS-CoV-2; COVID-19; Spike protein; Syncytia; Cell fusion; ACE2; Cell hybrid

Funding

  1. Rutgers-Health Advance Funding (NIH REACH program)
  2. Rutgers University-New Jersey Medical School
  3. [HL125018]
  4. [AI124769]
  5. [AI129594]
  6. [AI130197]
  7. [U01HL150852]
  8. [S10OD025182]

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The study investigated cell fusion events mediated by the S protein of SARS-CoV-2 and ACE2 interaction in different human cell lines, revealing that only certain cells expressing S protein can form syncytial structures. This cell-cell fusion process appears to be cell type-dependent and may rely on different parameters. The Delta 19-S variant shows defective nuclear fusion and syncytia formation compared to the wild-type S protein, which may have implications for pseudovirus-based entry assays and vaccine design strategies.
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 (Delta 19-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 Delta 19-S variant is being widely used to increase SARS-CoV-2 pseudovirus production for in vitro assays. Comparison of cell fusion occurring via Delta 19-S expressing cells shows defective nuclear fusion and syncytia formation compared to WT-S. Conclusions This distinction between the Delta 19-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. Delta 19-S mRNA may represent a safer mRNA vaccine design in the future.

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