SARS-CoV-2 Delta Spike Protein Enhances the Viral Fusogenicity and Inflammatory Cytokine Production

The Delta variant is now the most dominant and virulent SARS-CoV-2 variant of concern (VOC). In this study, we investigated several virological features of Delta spike protein (SP _Delta ), including protein maturation and its impact on viral entry of cell-free pseudotyped virus, cell-cell fusion ability and its induction of inflammatory cytokine production in human macrophages and dendritic cells. The results showed that SPΔC _Delta exhibited enhanced S1/S2 cleavage in cells and pseudotyped virus-like particles (PVLPs). We further showed that SPΔC _Delta elevated pseudovirus infection in human lung cell lines and mediated significantly enhanced syncytia formation. Furthermore, we revealed that SPΔC _Delta -PVLPs had stronger effects on stimulating NF-κB and AP-1 signaling in human monocytic THP1 cells and induced significantly higher levels of pro-inflammatory cytokine, such as TNF-α, IL-1β and IL-6, released from human macrophages and dendritic cells. Overall, these studies provide evidence to support the important role of SPΔC _Delta during virus infection, transmission and pathogenesis.