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

Author

Listed:
  • Qi Zhang

    (National Institutes of Health
    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
    Glycan Therapeutics Corp)

  • 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)

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.

Suggested Citation

  • 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 & , 2023. "Host heparan sulfate promotes ACE2 super-cluster assembly and enhances SARS-CoV-2-associated syncytium formation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41453-w
    DOI: 10.1038/s41467-023-41453-w
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