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SARS-CoV-2 spike N-terminal domain modulates TMPRSS2-dependent viral entry and fusogenicity

Abstract:

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike N-terminal domain (NTD) remains poorly characterized despite enrichment of mutations in this region across variants of concern (VOCs). Here, we examine the contribution of the NTD to infection and cell-cell fusion by constructing chimeric spikes bearing B.1.617 lineage (Delta and Kappa variants) NTDs and generating spike pseudotyped lentivirus. We find that the Delta NTD on a Kappa or wild-type (WT) background increases S1/S2 cleavage efficiency and virus entry, specifically in lung cells and airway organoids, through use of TMPRSS2. Delta exhibits increased cell-cell fusogenicity that could be conferred to WT and Kappa spikes by Delta NTD transfer. However, chimeras of Omicron BA.1 and BA.2 spikes with a Delta NTD do not show more efficient TMPRSS2 use or fusogenicity. We conclude that the NTD allosterically modulates S1/S2 cleavage and spike-mediated functions in a spike context-dependent manner, and allosteric interactions may be lost when combining regions from more distantly related VOCs.

Año de publicación:

2022

Keywords:

  • DELTA
  • Organoid
  • CP: Microbiology
  • entry
  • fusogenicity
  • SARS-COV-2
  • NTD
  • spike
  • Omicron
  • TMPRSS2

Fuente:

scopusscopus

Tipo de documento:

Article

Estado:

Acceso abierto

Áreas de conocimiento:

    Áreas temáticas:

    • Microorganismos, hongos y algas
    • Enfermedades
    • Farmacología y terapéutica

    Contribuidores:

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