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

Larisa I Labzin, Keng Yih Chew, Kathrin Eschke, Xiaohui Wang, Tyron Esposito, Claudia J Stocks, James Rae, Ralph Patrick, Helen Mostafavi, Brittany Hill, Teodor E Yordanov, Caroline L Holley, Stefan Emming, Svenja Fritzlar, Francesca L Mordant, Daniel P Steinfort, Kanta Subbarao, Christian M Nefzger, Anne K Lagendijk, Emma J Gordon, Robert G Parton, Kirsty R Short, Sarah L Londrigan, Kate Schroder

Macrophages are key cellular contributors to the pathogenesis of COVID-19, the disease caused by the virus SARS-CoV-2. The SARS-CoV-2 entry receptor ACE2 is present only on a subset of macrophages at sites of SARS-CoV-2 infection in humans. Here, we investigated whether SARS-CoV-2 can enter macrophages, replicate, and release new viral progeny; whether macrophages need to sense a replicating virus to drive cytokine release; and, if so, whether ACE2 is involved in these mechanisms. We found that SARS-CoV-2 could enter, but did not replicate within, ACE2-deficient human primary macrophages and did not induce proinflammatory cytokine expression. By contrast, ACE2 overexpression in human THP-1-derived macrophages permitted SARS-CoV-2 entry, processing and replication, and virion release. ACE2-overexpressing THP-1 macrophages sensed active viral replication and triggered proinflammatory, antiviral programs mediated by the kinase TBK-1 that limited prolonged viral replication and release. These findings help elucidate the role of ACE2 and its absence in macrophage responses to SARS-CoV-2 infection.