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Inhibition of SARS-CoV-2-mediated thromboinflammation by CLEC2.Fc

Pei-Shan Sung1, Cheng-Pu Sun2, Mi-Hua Tao2

  • 1Genomics Research Center, Academia Sinica, Taipei, Taiwan.

EMBO Molecular Medicine
|May 22, 2023
PubMed

Insights

The C-type lectin member 2 (CLEC2) receptor on platelets directly interacts with SARS-CoV-2, driving harmful thromboinflammation and NET formation. CLEC2.Fc therapy shows promise in preventing these COVID-19 complications.

Area of Science:

  • Immunology
  • Virology
  • Hematology

Background:

  • Thromboinflammation is a primary driver of severe COVID-19 morbidity and mortality.
  • Persistent microclots are observed in both acute and long COVID, but the underlying molecular mechanisms remain elusive.
  • Understanding SARS-CoV-2 interactions with host factors is crucial for developing effective treatments.

Purpose of the Study:

  • To elucidate the molecular mechanism of SARS-CoV-2-induced thromboinflammation.
  • To identify host receptors involved in SARS-CoV-2 platelet activation and NET formation.
  • To evaluate the therapeutic potential of targeting identified pathways.

Main Methods:

  • Investigated the interaction between SARS-CoV-2 spike protein receptor-binding domain (RBD) and C-type lectin member 2 (CLEC2) on platelets and macrophages.
  • Assessed SARS-CoV-2-induced neutrophil extracellular trap (NET) formation in the presence of wild-type versus CLEC2-deficient platelets.
  • Utilized SARS-CoV-2 spike pseudotyped lentivirus to induce NET formation.
  • Administered CLEC2.Fc to AAV-ACE2-infected mice to evaluate its effect on thromboinflammation.

Main Results:

  • CLEC2, highly expressed in platelets and alveolar macrophages, directly binds to the SARS-CoV-2 RBD.
  • SARS-CoV-2 induces aggregated NET formation dependent on CLEC2-expressing platelets.
  • CLEC2 engagement by SARS-CoV-2 RBD activates platelets, enhancing NET formation.
  • CLEC2.Fc administration successfully inhibited SARS-CoV-2-induced NET formation and thromboinflammation in vivo.

Conclusions:

  • CLEC2 acts as a novel pattern recognition receptor for SARS-CoV-2.
  • Targeting the CLEC2-SARS-CoV-2 interaction with CLEC2.Fc may offer a therapeutic strategy against COVID-19-associated thromboinflammation.
  • This approach could potentially reduce the risk of post-acute sequelae of COVID-19 (PASC).

Keywords:
CLEC2NETSARS-CoV-2plateletthromboinflammation

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