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Macrophage ACE2 is necessary for SARS-CoV-2 replication and subsequent cytokine responses that restrict continued

Larisa I Labzin1,2,3, Keng Yih Chew4, Kathrin Eschke1

  • 1Institute for Molecular Bioscience (IMB), University of Queensland, Brisbane, QLD 4072, Australia.

Science Signaling
|April 25, 2023
PubMed

Insights

Macrophages lacking ACE2 resist SARS-CoV-2 infection. Overexpressing ACE2 enables viral replication and triggers immune responses, revealing ACE2

Area of Science:

  • Immunology
  • Virology
  • Cell Biology

Background:

  • Macrophages are crucial in COVID-19 pathogenesis.
  • SARS-CoV-2 entry receptor ACE2 is sparsely expressed on human macrophages at infection sites.

Purpose of the Study:

  • Investigate SARS-CoV-2 entry, replication, and cytokine release in macrophages.
  • Determine the role of ACE2 in these macrophage responses to SARS-CoV-2.

Main Methods:

  • Utilized ACE2-deficient human primary macrophages and ACE2-overexpressing THP-1 derived macrophages.
  • Assessed SARS-CoV-2 entry, replication, virion release, and cytokine expression.
  • Examined the involvement of the kinase TBK-1 in macrophage antiviral programs.

Main Results:

  • SARS-CoV-2 entered but did not replicate in ACE2-deficient macrophages, without inducing cytokine release.
  • ACE2 overexpression facilitated SARS-CoV-2 entry, replication, and virion release in THP-1 macrophages.
  • ACE2-overexpressing macrophages detected viral replication, activating TBK-1-mediated antiviral programs that limited viral spread.

Conclusions:

  • ACE2 expression dictates macrophage susceptibility to SARS-CoV-2 infection and subsequent immune responses.
  • The absence of ACE2 on macrophages limits viral replication and pro-inflammatory cytokine production.
  • ACE2-mediated sensing of viral replication activates macrophage antiviral defenses, influencing COVID-19 pathogenesis.

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