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SARS-CoV-2 down-regulates ACE2 through lysosomal degradation.

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|October 26, 2022
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection down-regulates angiotensin-converting enzyme 2 (ACE2) via endocytosis, leading to pathology. A soluble ACE2 fragment blocks this down-regulation and viral infection, offering a therapeutic strategy.

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Area of Science:

  • Virology
  • Cell Biology
  • Immunology

Background:

  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses its Spike (S) glycoprotein to enter cells via the angiotensin-converting enzyme 2 (ACE2) receptor.
  • ACE2 regulates the renin-angiotensin system and protects against tissue injury.
  • Previous studies showed SARS-CoV down-regulates ACE2, but the mechanism and impact for SARS-CoV-2 were unclear.

Purpose of the Study:

  • To investigate whether SARS-CoV-2 down-regulates ACE2.
  • To elucidate the mechanism and biological impact of ACE2 down-regulation by SARS-CoV-2.
  • To identify potential therapeutic strategies targeting ACE2 down-regulation.

Main Methods:

  • In vivo animal model and in vitro cultured cells were used to study ACE2 expression after SARS-CoV-2 infection.
  • Clathrin- and AP2-dependent endocytosis pathways were investigated.
  • Downstream gene expression and cytokine signaling were analyzed.
  • A soluble ACE2 fragment was tested for its ability to block viral infection and ACE2 down-regulation.

Main Results:

  • SARS-CoV-2 infection was shown to down-regulate ACE2 in both animal models and cultured cells.
  • The down-regulation mechanism involves clathrin- and AP2-dependent endocytosis, leading to lysosomal degradation of ACE2.
  • ACE2 down-regulation induced gene expression patterns similar to those seen in cytokine signaling, associated with respiratory distress in COVID-19 patients.
  • A soluble ACE2 fragment effectively blocked ACE2 down-regulation and SARS-CoV-2 infection.

Conclusions:

  • ACE2 down-regulation is a key mechanism contributing to SARS-CoV-2-associated pathology.
  • Targeting and blocking ACE2 down-regulation presents a promising therapeutic avenue for COVID-19.
  • The identified soluble ACE2 fragment could be a potential therapeutic agent.