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Plasmacytoid dendritic cells (pDCs), a key cell type involved in antiviral responses, can produce IFN-I in response to SARS-CoV-2. We observed the infiltration of pDCs in the lungs of SARS-CoV-2\u2013infected patients, which correlated with strong IFN-I signaling in lung macrophages. In patients with severe COVID-19, lung macrophages expressed a robust inflammatory signature, which correlated with persistent IFN-I signaling at the single-cell level. Hence, we observed the uncoupling in the kinetics of the infiltration of pDCs in the lungs and the associated IFN-I signature, with the cytokine storm in macrophages. We observed that pDCs were the dominant IFN-\u03b1\u2013producing cells in response to the virus in the blood, whereas macrophages produced IFN-\u03b1 only when in physical contact with infected epithelial cells. We also showed that IFN-\u03b1 produced by pDCs, after the sensing of SARS-CoV-2 by TLR7, mediated changes in macrophages at both transcriptional and epigenetic levels, which favored their hyperactivation by environmental stimuli. Together, these data indicate that the priming of macrophages can result from the response by pDCs to SARS-CoV-2, leading to macrophage activation in patients with severe COVID-19.<\/jats:p>","DOI":"10.1126\/sciimmunol.add4906","type":"journal-article","created":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T13:58:33Z","timestamp":1662731913000},"source":"Crossref","is-referenced-by-count":84,"title":["Sensing of SARS-CoV-2 by pDCs and their subsequent production of IFN-I contribute to macrophage-induced cytokine storm during COVID-19"],"prefix":"10.1126","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7102-2184","authenticated-orcid":true,"given":"Pa\u00f4line","family":"Laurent","sequence":"first","affiliation":[{"name":"HSS Research Institute and David Z.\u00a0Rosensweig Genomics Research Center, Hospital for Special Surgery, New\u00a0York, NY 10021, 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