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Cellular sialoglycans are differentially required for endosomal and cell-surface entry of SARS-CoV-2 in lung cell

Kimberley C Siwak1, Emmanuelle V LeBlanc1, Heidi M Scott1

  • 1Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Canada.

Plos Pathogens
|December 3, 2024
PubMed

Insights

Cellular sialoglycans promote endosomal entry for SARS-CoV-2 and related viruses, but are not essential for cell surface entry. This clarifies the role of sialic acid in viral cell entry pathways.

Area of Science:

  • Virology
  • Cell Biology
  • Biochemistry

Background:

  • Severe acute respiratory coronavirus-2 (SARS-CoV-2) and other coronaviruses (CoVs) utilize distinct cell entry routes.
  • Entry involves spike glycoprotein binding and membrane fusion, triggered by cleavage at the cell surface (TMPRSS2-dependent) or within endosomes (cathepsin-dependent).
  • The role of cellular sialoglycans in these distinct CoV entry pathways remains unclear.

Purpose of the Study:

  • To investigate the functional contribution of cellular sialoglycans to SARS-CoV-2 and related sarbecovirus entry via endosomal and cell-surface pathways.
  • To compare the requirement for sialoglycans in different CoV entry routes and their dependence on host proteases like TMPRSS2 and cathepsins.

Main Methods:

  • Genetic and enzymatic depletion of sialic acid from cell surfaces.
  • Use of lentiviral particles pseudotyped with spike proteins from various sarbecoviruses (SARS-CoV-1, WIV1-CoV, WIV16-CoV, SARS-CoV-2 variants).
  • Comparison of CoV entry efficiency in the presence or absence of sialic acid and under varying protease expression conditions (TMPRSS2, cathepsins).

Main Results:

  • Entry of SARS-CoV-1, WIV1-CoV, WIV16-CoV, and SARS-CoV-2 Omicron variant requires endosomal cathepsins and cellular sialoglycans.
  • Ancestral SARS-CoV-2 and Delta variants use both entry pathways but require sialic acid only for endosomal entry when TMPRSS2 is absent.
  • Sialic acid is not required for SARS-CoV-2 spike protein binding or entry into TMPRSS2-expressing cells, indicating it promotes endocytic entry rather than attachment or fusion.

Conclusions:

  • Cellular sialoglycans are not essential for SARS-CoV-2 attachment, receptor binding, or fusion, but specifically promote endocytic entry.
  • The requirement for sialic acid varies depending on the specific CoV, entry pathway, and host cell protease expression.
  • Findings clarify that sialoglycans mediate endosomal, but not cell-surface, entry for SARS-CoV-2 and related sarbecoviruses.

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