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

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 macropha...

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Published inScience signaling Vol. 16; no. 782; p. eabq1366
Main Authors Labzin, Larisa I, Chew, Keng Yih, Eschke, Kathrin, Wang, Xiaohui, Esposito, Tyron, Stocks, Claudia J, Rae, James, Patrick, Ralph, Mostafavi, Helen, Hill, Brittany, Yordanov, Teodor E, Holley, Caroline L, Emming, Stefan, Fritzlar, Svenja, Mordant, Francesca L, Steinfort, Daniel P, Subbarao, Kanta, Nefzger, Christian M, Lagendijk, Anne K, Gordon, Emma J, Parton, Robert G, Short, Kirsty R, Londrigan, Sarah L, Schroder, Kate
Format Journal Article
LanguageEnglish
Published United States 25.04.2023
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Summary: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.
ISSN:1937-9145
DOI:10.1126/scisignal.abq1366