Host heparan sulfate promotes ACE2 super-cluster assembly and enhances SARS-CoV-2-associated syncytium formation

Qi Zhang, Weichun Tang, Eduardo Stancanelli, Eunkyung Jung, Zulfeqhar Syed, Vijayakanth Pagadala, Layla Saidi, Catherine Z. Chen, Peng Gao, Miao Xu, Ivan Pavlinov, Bing Li, Wenwei Huang, Liqiang Chen, Jian Liu, Hang Xie, Wei Zheng and Yihong Ye ()
Additional contact information
Qi Zhang: National Institutes of Health
Weichun Tang: Food and Drug Administration
Eduardo Stancanelli: University of North Carolina
Eunkyung Jung: University of Minnesota
Zulfeqhar Syed: National Institutes of Health
Vijayakanth Pagadala: University of North Carolina
Layla Saidi: National Institutes of Health
Catherine Z. Chen: National Institutes of Health
Peng Gao: National Institutes of Health
Miao Xu: National Institutes of Health
Ivan Pavlinov: National Institutes of Health
Bing Li: National Institutes of Health
Wenwei Huang: National Institutes of Health
Liqiang Chen: University of Minnesota
Jian Liu: University of North Carolina
Hang Xie: Food and Drug Administration
Wei Zheng: National Institutes of Health
Yihong Ye: National Institutes of Health

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract SARS-CoV-2 infection causes spike-dependent fusion of infected cells with ACE2 positive neighboring cells, generating multi-nuclear syncytia that are often associated with severe COVID. To better elucidate the mechanism of spike-induced syncytium formation, we combine chemical genetics with 4D confocal imaging to establish the cell surface heparan sulfate (HS) as a critical stimulator for spike-induced cell-cell fusion. We show that HS binds spike and promotes spike-induced ACE2 clustering, forming synapse-like cell-cell contacts that facilitate fusion pore formation between ACE2-expresing and spike-transfected human cells. Chemical or genetic inhibition of HS mitigates ACE2 clustering, and thus, syncytium formation, whereas in a cell-free system comprising purified HS and lipid-anchored ACE2, HS stimulates ACE2 clustering directly in the presence of spike. Furthermore, HS-stimulated syncytium formation and receptor clustering require a conserved ACE2 linker distal from the spike-binding site. Importantly, the cell fusion-boosting function of HS can be targeted by an investigational HS-binding drug, which reduces syncytium formation in vitro and viral infection in mice. Thus, HS, as a host factor exploited by SARS-CoV-2 to facilitate receptor clustering and a stimulator of infection-associated syncytium formation, may be a promising therapeutic target for severe COVID.

Date: 2023
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DOI: 10.1038/s41467-023-41453-w

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