SARS-CoV-2 S1 protein induces IgG-mediated platelet activation and is prevented by 1.8-cineole

COVID-19 patients face an increased risk of thromboembolic complications, yet the exact pathophysiological role of platelets in the disease remains unclear. Considering the multifaceted nature of COVID-19 symptoms, including platelet hyperactivation and inflammation, the development of compounds that simultaneously target both represents a promising therapeutic strategy. The monoterpene 1.8-cineole (CNL-1976) is known for its anti-inflammatory and anti-aggregatory effects. Thus, understanding the mechanism behind platelet hyperactivation and the effect of 1.8-cineole during COVID-19 is crucial when aiming for a reduction of disease severity. In this study, we investigated the mechanism of platelet activation triggered by the SARS-CoV-2 S1 spike protein (S1). Utilizing S1-coupled beads, we discovered that platelet activation and aggregation were dependent on plasma components, particularly S1-specific IgG antibodies. The formation of immune complexes through IgG binding to S1 facilitated the crosslinking of the platelet expressed FcγRIIa receptor, initiating platelet activation and aggregation, as well as formation of platelet-leukocyte aggregates (PLAs). Importantly, treatment with 1.8-cineole significantly inhibited S1-bead-induced platelet activity and PLA formation. These findings strongly suggest that antibody-mediated platelet activation via FcγRIIa directly contributes to the well-recognized prothrombotic environment during COVID-19. Moreover, our data indicate that 1.8-cineole can serve as a potential therapeutic compound, alleviating platelet-driven thromboinflammatory complications associated with COVID-19 and post-acute sequelae of SARS-CoV-2 (PASC).