Induction of Cell-Cell Fusion

Stable Identifier
R-HSA-9733458
Type
Pathway
Species
Homo sapiens
Related Species
Severe acute respiratory syndrome coronavirus 2
Compartment
plasma membrane
ReviewStatus
5/5
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Induction of Cell-Cell Fusion
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Many enveloped viruses induce multinucleated cells (syncytia) in later stages of viral infection. The membrane fusion that drives these cell-cell fusion events are caused by the same machinery that underlies viral entry. The presence of infected syncytial pneumocytes in severe COVID-19 patients is well established (Zhang et al., 2021). However, it is currently unclear if syncytia formation is also a feature of milder or asymptomatic SARS-CoV-2 infections. These syncytia are also thought to facilitate replication and evasion of the host immune response (for a recent review on Spike-mediated fusion and syncytia formation see Rajah et al, 2022). Experiments that utilize co-cultures of human cells expressing the receptor ACE2 with cells expressing SARS-CoV-2 spike protein, result in synapse-like intercellular contacts that initiate cell-cell fusion, producing syncytia resembling those we identify in lungs of COVID-19 patients (Sanders et al., 2021). Studies on SARS-CoV-2 identified similar syncytia (Buchrieser et al., 2020; Hoffmann et al., 2020a; Ou et al., 2020; Xia et al., 2020). Formation of the ACE2/spike protein complex drives fusion events that proceed from finger-like projections, forming synapses between cells to development of a fusion pore and subsequent membrane fusion (reviewed in Rajah et al, 2022; Rey, 2021). Notably cleaving the spike protein into S1 and S2 sub-fragments appears to increase the probability of S1/ACE2 fusion (Hoffmann et al., 2020a).
The Alpha, Beta, and Delta variants of SARS-CoV-2 display enhanced syncytia formation (Cheng et al, 2021; Rajah et al, 2021). An additional phenomenon with SARS-CoV-2 syncytia is their targeting of lymphocytes for internalization and cell-in-cell mediated elimination, potentially contributing to lymphopenia and pathogenesis in COVID-19 patients (Zhang et al, 2021).
Literature References
PubMed ID Title Journal Year
33051876 Syncytia formation by SARS-CoV-2-infected cells

Buchrieser, J, Dufloo, J, Hubert, M, Monel, B, Planas, D, Rajah, MM, Planchais, C, Porrot, F, Guivel-Benhassine, F, van der Werf, S, Casartelli, N, Mouquet, H, Bruel, T, Schwartz, O

EMBO J 2020
33879858 SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte elimination

Zhang, Z, Zheng, Y, Niu, Z, Zhang, B, Wang, C, Yao, X, Peng, H, Franca, DN, Wang, Y, Zhu, Y, Su, Y, Tang, M, Jiang, X, Ren, H, He, M, Wang, Y, Gao, L, Zhao, P, Shi, H, Chen, Z, Wang, X, Piacentini, M, Bian, X, Melino, G, Liu, L, Huang, H, Sun, Q

Cell Death Differ 2021
32221306 Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV

Ou, X, Liu, Y, Lei, X, Li, P, Mi, D, Ren, L, Guo, L, Guo, R, Chen, T, Hu, J, Xiang, Z, Mu, Z, Chen, X, Chen, J, Hu, K, Jin, Q, Wang, J, Qian, Z

Nat Commun 2020
33890572 SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation

Sanders, DW, Jumper, CC, Ackerman, PJ, Bracha, D, Donlic, A, Kim, H, Kenney, D, Castello-Serrano, I, Suzuki, S, Tamura, T, Tavares, AH, Saeed, M, Holehouse, AS, Ploss, A, Levental, I, Douam, F, Padera, RF, Levy, BD, Brangwynne, CP

Elife 2021
34606831 The Mechanism and Consequences of SARS-CoV-2 Spike-Mediated Fusion and Syncytia Formation

Rajah, MM, Bernier, A, Buchrieser, J, Schwartz, O

J Mol Biol 2022
32231345 Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion

Xia, S, Liu, M, Wang, C, Xu, W, Lan, Q, Feng, S, Qi, F, Bao, L, Du, L, Liu, S, Qin, C, Sun, F, Shi, Z, Zhu, Y, Jiang, S, Lu, L

Cell Res 2020
34311586 D614G Substitution of SARS-CoV-2 Spike Protein Increases Syncytium Formation and Virus Titer via Enhanced Furin-Mediated Spike Cleavage

Cheng, YW, Chao, TL, Li, CL, Wang, SH, Kao, HC, Tsai, YM, Wang, HY, Hsieh, CL, Lin, YY, Chen, PJ, Chang, SY, Yeh, SH

mBio 2021
32362314 A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells

Hoffmann, M, Kleine-Weber, H, Pöhlmann, S

Mol. Cell 2020
34601723 SARS-CoV-2 Alpha, Beta, and Delta variants display enhanced Spike-mediated syncytia formation

Rajah, MM, Hubert, M, Bishop, E, Saunders, N, Robinot, R, Grzelak, L, Planas, D, Dufloo, J, Gellenoncourt, S, Bongers, A, Zivaljic, M, Planchais, C, Guivel-Benhassine, F, Porrot, F, Mouquet, H, Chakrabarti, LA, Buchrieser, J, Schwartz, O

EMBO J 2021
34213849 Structure-function relations of the SARS-CoV-2 spike protein and impact of mutations in the variants of concern

Rey, F

C R Biol 2021
Participants
Events
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as an event of
Event Information
Go Biological Process
symbiont-mediated induction of syncytium formation (0060141)
Disease
Name Identifier Synonyms
COVID-19 DOID:0080600 2019 Novel Coronavirus (2019-nCoV), Wuhan seafood market pneumonia virus infection, 2019-nCoV infection, Wuhan coronavirus infection
Cross References
Mondo
Authored
Stephan, R  (2022-08-05)
Reviewed
Gillespie, ME  (2022-05-10)
Created
Stephan, R  (2021-06-04)
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