DC/L-SIGN recognition of spike glycoprotein promotes SARS-CoV-2 trans-infection and can be inhibited by a glycomimetic antagonist

PLoS Pathog. 2021 May 20;17(5):e1009576. doi: 10.1371/journal.ppat.1009576. eCollection 2021 May.

Abstract

The efficient spread of SARS-CoV-2 resulted in a unique pandemic in modern history. Despite early identification of ACE2 as the receptor for viral spike protein, much remains to be understood about the molecular events behind viral dissemination. We evaluated the contribution of C-type lectin receptors (CLRS) of antigen-presenting cells, widely present in respiratory mucosa and lung tissue. DC-SIGN, L-SIGN, Langerin and MGL bind to diverse glycans of the spike using multiple interaction areas. Using pseudovirus and cells derived from monocytes or T-lymphocytes, we demonstrate that while virus capture by the CLRs examined does not allow direct cell infection, DC/L-SIGN, among these receptors, promote virus transfer to permissive ACE2+ Vero E6 cells. A glycomimetic compound designed against DC-SIGN, enable inhibition of this process. These data have been then confirmed using authentic SARS-CoV-2 virus and human respiratory cell lines. Thus, we described a mechanism potentiating viral spreading of infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • COVID-19 / prevention & control
  • COVID-19 / transmission*
  • Cell Adhesion Molecules / metabolism
  • Cell Line
  • Chlorocebus aethiops
  • Humans
  • Jurkat Cells
  • Lectins, C-Type / metabolism*
  • Lung / metabolism
  • Mannose-Binding Lectins / metabolism
  • Mannosides / pharmacology
  • Protein Binding / drug effects
  • Receptors, Cell Surface / metabolism
  • Respiratory Mucosa / metabolism
  • SARS-CoV-2 / metabolism*
  • Spike Glycoprotein, Coronavirus / metabolism*
  • Vero Cells

Substances

  • Antigens, CD
  • CD207 protein, human
  • CLEC4M protein, human
  • Cell Adhesion Molecules
  • DC-specific ICAM-3 grabbing nonintegrin
  • Lectins, C-Type
  • MGL lectin, human
  • Mannose-Binding Lectins
  • Mannosides
  • Receptors, Cell Surface
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2

Grant support

This work used the platforms of the Grenoble Instruct-ERIC centre (ISBG; UMS 3518 CNRS-CEA-UGA-EMBL) within the Grenoble Partnership for Structural Biology (PSB), supported by FRISBI (ANR-10-INBS-05-02) and GRAL, within the University Grenoble Alpes graduate school CBH-EUR-GS (ANR-17-EURE-0003). The EM facility is supported by the Auvergne-Rhône-Alpes Region, the Fondation Recherche Medicale, the fonds FEDER and the GIS-Infrastructures Biologie Sante et Agronomie (IBISA). F.F. acknowledges the French Agence Nationale de la Recherche PIA for Glyco@Alps (ANR-15-IDEX-02). Research in R.D. lab is supported by grants from the Instituto de Investigación Carlos III, ISCIII, (FIS PI 1801007), the European Commission Horizon 2020 Framework Programme: Project VIRUSCAN FETPROACT-2016: 731868, and by Fundación Caixa-Health Research (Project StopEbola). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.