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 Steinfort, Kanta Subbarao, Christian M. Nefzger, Anne K. Lagendijk, Emma Gordon, Robert G. Parton, Kirsty R. Short, Sarah L. Londrigan, Kate Schroder
Abstract
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.