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

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. ### Competing Interest Statement KRS is a consultant for Sanofi, Roche and NovoNordisk. K. Schroder is a co-inventor on patent applications for NLRP3 inhibitors which have been licensed to Inflazome Ltd, a company headquartered in Dublin, Ireland. Inflazome is developing drugs that target the NLRP3 inflammasome to address unmet clinical needs in inflammatory disease. K. Schroder served on the Scientific Advisory Board of Inflazome in 2016-2017, and serves as a consultant to Quench Bio, USA and Novartis, Switzerland.