Macrophage phagocytosis of SARS-CoV-2-infected cells mediates potent plasmacytoid dendritic cell activation

Early and strong interferon type I (IFN-I) responses are usually associated with mild COVID-19 disease, whereas persistent orunregulated proinflammatory cytokine responses are associated with severe disease outcomes. Previous work suggested thatmonocyte-derived macrophages (MDMs) are resistant and unresponsive to SARS-CoV-2 infection. Here, we demonstrate that uponphagocytosis of SARS-CoV-2-infected cells, MDMs are activated and secrete IL-6 and TNF. Importantly, activated MDMs in turnmediate strong activation of plasmacytoid dendritic cells (pDCs), leading to the secretion of high levels of IFN-α and TNF.Furthermore, pDC activation promoted IL-6 production by MDMs. This kind of pDC activation was dependent on direct integrinmediated cell‒cell contacts and involved stimulation of the TLR7 and STING signaling pathways. Overall, the present studydescribes a novel and potent pathway of pDC activation that is linked to the macrophage-mediated clearance of infected cells.These findings suggest that a high infection rate by SARS-CoV-2 may lead to exaggerated cytokine responses, which maycontribute to tissue damage and severe disease.