ABSTRACT
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains an important health threat. Syncytial formation by infected cells mediated by the SARS-CoV-2 spike protein (SARS-2-S) is a hallmark of COVID-19-associated pathology. Although SARS-CoV-2 infection evokes cellular senescence, as in other viruses, the direct link between SARS-2-S-induced syncytia with senescence in the absence of viral infection and their senescence fate determinants remain unknown. Here, we show that syncytia formed by cells expressing exogenously delivered SARS-2-S exhibited a senescence-like phenotype in vitro and that SARS-2-S mRNA induced senescence phenotype in vivo. Extracellular vesicles (EVs) containing SARS-2-S also induced senescent syncytium formation independent of the de novo synthesis of SARS-2-S. Mechanistically, we show that the accumulation of endogenous dsRNA, partially that whose formation is induced by activation of the unfolded protein response (UPR), in SARS-2-S syncytia triggers RIG-I-MAVS signalling to drive the TNF-α-dependent survival and senescence fate of SARS-2-S syncytia. Our findings suggest that the fusogenic ability of SARS-2-S might contribute to the side effects of particular COVID-19 vaccines or perhaps long COVID-19 syndrome and provide insight into how these effects can be prevented.