ABSTRACT
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.