SARS-CoV-2 Envelope protein (E) binds and activates TLR2: A novel target for COVID-19 interventions

In this study, we present a molecular characterization of the interaction between the SARS-CoV-2 envelope protein E with TLR2. We demonstrated that E protein interacts physically with TLR2 receptor in a specific and dose-dependent manner. Furthermore, we showed that this interaction is able to engage TLR2 pathway as demonstrated by its capacity to activate NF-κB transcription factor and to stimulate the production of CXCL8 inflammatory chemokine in a TLR2-dependent manner. Furthermore, in agreement with the importance of NF-κB in TLR signaling pathway, we showed that the chemical inhibition of this transcription factor led to significant inhibition of CXCL8 production, while blockade of P38 and ERK1/2 MAP kinases resulted only in a partial CXCL8 inhibition. Overall, our findings suggest considering the envelope protein E as a novel target for COVID-19 interventions: ( i ) either by exploring the therapeutic effect of anti-E blocking/neutralizing antibodies in symptomatic COVID-19 patients, or ( ii ) as a promising non-Spike SARS-CoV-2 antigen candidate to include in the development of next generation prophylactic vaccines against COVID-19 infection and disease. Importance Although, the exact mechanisms of COVID-19 pathogenesis are unknown, recent data demonstrated that elevated levels of pro-inflammatory cytokines in serum is associated with enhanced disease pathogenesis and mortality. Thus, determining the molecular mechanisms responsible for inflammatory cytokine production in the course of SARS-CoV-2 infection could provide future therapeutic targets. In this context, to the best of our knowledge, our report is first to use a detailed molecular characterization to demonstrate that SARS-CoV-2 Envelope E protein binds to TLR2 receptor. Specifically, we showed that SARS-CoV-2 Envelope E protein binds to TLR2 in a direct, specific and dose-dependent manner. Investigating signalling events that control downstream activation of cytokine production show that E protein / TLR2 binding leads to the activation of NF-κB transcription factor that control the expression of multiple pro-inflammatory cytokines including CXCL8. Overall, our findings suggest considering the envelope protein E as a novel target for COVID-19 interventions.