TNF inhibits SARS-CoV-2 induced cell-cell fusion through activating the SDC4-RhoA signaling to promote actin bundles formation.

SARS-CoV-2 infection-induced syncytia formation accelerates cell-to-cell transmission of the virus and enhances viral evasion by neutralizing antibodies. Host innate immune response plays a key role in controlling viral infection. Our present work identifies tumor necrosis factor (TNF) as a key cytokine quickly released from activated innate immune cells that suppresses SARS-CoV-2 spike-mediated cell-cell fusion. Mechanistically, TNF signals through the TNFR1-TRADD/TRAF2/RIPK1-MAPK-SDC4 axis. SDC4 further activates the RhoA/ROCK signaling pathway, which promotes cytoskeletal reorganization, leading to the formation of actin bundles at the interface between infected cell and adjacent cell. Such remodeling of actin effectively blocks further propagation of syncytia and viral spreading. These findings provide critical insights into the dynamic interplay between host antiviral factors and syncytia formation, deepening our understanding of the innate immune control of SARS-CoV-2 infection.