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

## TL;DR

TNF, a key immune cytokine, prevents SARS-CoV-2 from causing cell-cell fusion by activating a signaling pathway that forms actin barriers.

## Contribution

Identifies TNF as a novel antiviral factor that inhibits SARS-CoV-2-induced cell fusion via the SDC4-RhoA signaling pathway.

## Key findings

- TNF suppresses cell-cell fusion caused by various SARS-CoV-2 Spike variants across multiple cell types.
- TNF activates the TNFR1-TRADD/TRAF2/RIPK1-MAPK-SDC4 axis to inhibit membrane fusion.
- SDC4/RhoA/ROCK signaling promotes actin bundle formation, creating a mechanical barrier against syncytia.

## Abstract

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.

Image 1

•TNF effectively suppresses cell-cell fusion induced by various SARS-CoV-2 Spike variants across multiple cell types.•As a primary inflammatory cytokine, TNF is released early during innate immune cell activation to restrict membrane fusion.•TNF signals through the TNFR1 receptor and the TRADD/TRAF2/RIPK1 complex, subsequently activating the MAPK and SDC4 pathways to inhibit cell-cell fusion.•Downstream signaling of SDC4/RhoA/ROCK triggered by TNF promotes actin bundle formation, creating a mechanical barrier against cell-cell fusion.

TNF effectively suppresses cell-cell fusion induced by various SARS-CoV-2 Spike variants across multiple cell types.

As a primary inflammatory cytokine, TNF is released early during innate immune cell activation to restrict membrane fusion.

TNF signals through the TNFR1 receptor and the TRADD/TRAF2/RIPK1 complex, subsequently activating the MAPK and SDC4 pathways to inhibit cell-cell fusion.

Downstream signaling of SDC4/RhoA/ROCK triggered by TNF promotes actin bundle formation, creating a mechanical barrier against cell-cell fusion.