TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines

The innate immune response is critical for recognizing and controlling infections through the release of cytokines and chemokines. However, severe pathology during some infections, including SARS-CoV-2, is driven by hyperactive cytokine release, or cytokine storm. The innate sensors that activate production of pro-inflammatory cytokines and chemokines during COVID-19 remain poorly characterized. Here we show that both TLR2 and MYD88 expression were associated with COVID-19 disease severity. Mechanistically, TLR2 and MyD88 were required for β-coronavirus–induced inflammatory responses, and TLR2-dependent signaling induced the production of pro-inflammatory cytokines during coronavirus infection independent of viral entry. TLR2 sensed the SARS-CoV-2 envelope protein as its ligand. Additionally, blocking TLR2 signaling in vivo provided protection against the pathogenesis of SARS-CoV-2 infection. Overall, our study provides a critical understanding of the molecular mechanism of β-coronavirus sensing and inflammatory cytokine production, which opens new avenues for therapeutic strategies to counteract the ongoing COVID-19 pandemic.