Poster Presentation Hunter Cell Biology Meeting 2022

ACE2 is necessary for SARS-CoV-2 infection and sensing by macrophages but not sufficient for productive viral replication (#70)

Larisa Labzin 1 , Keng Yih Chew 2 , Xiaohui Wang 1 , Tyron Esposito 1 , Claudia Stocks 1 , James Rae 1 , Teodor Yordanov 1 , Caroline Holley 1 , Stefan Emming 1 , Svenja Fritzlar 3 , Francesca L Mordant 3 , Daniel Steinfort 4 , Kanta Subbarao 3 , Anne Karine Lagendijk 1 , Robert Parton 1 , Kirsty Short 2 , Sarah Londrigan 3 , Kate Schroder 1
  1. Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
  2. School of Chemistry and Molecular Biology, The University of Queensland, Brisbane, QLD, Australia
  3. Dept of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
  4. Department of Medicine, The University of Melbourne , Melbourne, Victoria, Australia

Macrophages are a major source of pro-inflammatory cytokines in COVID-19. How macrophages sense the causative virus, SARS-CoV-2, to drive cytokine release is, however, unclear. Here, we show that human macrophages do not directly sense and respond to infectious SARS-CoV-2 virions because they lack sufficient ACE2 expression to support virus entry and replication. Over-expression of ACE2 in human macrophages permits SARS-CoV-2 entry and early-stage replication and facilitates macrophage pro-inflammatory and anti-viral responses. ACE2 over-expression does not, however, permit the release of newly synthesised virions from SARS-CoV-2-infected macrophages, consistent with abortive replication. Release of new, infectious SARS-CoV-2 virions from ACE2 over-expressing macrophages only occurred if anti-viral mediator induction was also blocked, indicating that macrophages restrict SARS-CoV-2 infection at two stages of the viral life cycle. These findings resolve the current controversy over macrophage-SARS-CoV-2 interactions and identify a signalling circuit that directly links macrophage recognition of SARS-CoV-2 to restriction of viral replication.