Platelets Mediate Monocyte Inflammatory And Procoagulant Response By SARS-CoV-2 Spike Protein

Since late 2019,the global COVID-19 pandemic caused by SARS-CoV-2 has precipitated a profound public health crisis.Despite the successful implementation of interventions such as vaccination,COVID-19 remains a formidable global health menace,with over 700 million confirmed cases worldwide.While most infected individuals remain asymptomatic or experience mild symptoms,severe and critical cases can culminate in respiratory failure and mortality.These patients also exhibit systemic inflammation and abnormal blood clotting.However,the intricate interplay between coagulation and inflammatory responses in COVID-19 patients remains incompletely understood.Platelets,essential for pathogen recognition,play a pivotal role in both coagulant and inflammatory responses.Numerous studies have demonstrated that COVID-19 patients experience platelet activation,and the degree of activation correlates with disease severity.Conversely,severe patients manifest the infiltration of inflammatory monocytes in bronchoalveolar lavage fluid,directly associated with inflammatory manifestations.In addition,tissue factor(TF)released by monocytes directly initiates the generation of intravascular thrombin,mediating the amplification of coagulation reactions and the stabilization of blood clots.In infections such as influenza,dengue fever,and sepsis,the interaction between platelets and monocytes contributes to pathogen recognition,tissue factor activation,inflammatory coagulation pathways,and immune thrombosis.Consequently,this study aims to elucidate the direct effects of SARS-CoV-2 on platelets and monocytes,shedding light on the intricate thrombotic and inflammatory mechanisms underlying COVID-19.Firstly,our investigation revealed that platelets directly recognize the SARS-CoV-2 spike protein.By utilizing recombinant spike protein and pseudovirus particles expressing the spike protein,we observed that platelets from healthy individuals directly recognize the spike protein and undergo activation.This activation manifests as increased platelet aggregation,enhanced fibrinogen binding capacity,and elevated levels of P-selectin and CD40 L on the cell membrane.Secondly,the spike protein directly binds to and activates the CD42 b receptor on platelets.CD42 b,expressed by platelets,interacts directly with the spike protein’s receptor-binding domain,facilitating the spike protein’s adherence to the platelet cell membrane.Furthermore,the spike protein activates downstream signaling pathways,PI3K/Akt/PKC,via CD42 b.This activation leads to CD40 L expression.And,through an as-yet-unknown signaling pathway,the spike protein promotes P-selectin expression.Notably,ACE-2 is not involved in this process.Thirdly,the interaction between spike protein-activated platelets and monocytes leads to monocyte inflammatory responses and tissue factor release.Monocytes lacking ACE-2 or CD42 b cannot directly recognize the spike protein or secrete cytokines.In an in vitro co-culture model,we observed that spike protein-activated platelets bind to monocytes via P-selectin/PSGL-1.Under the co-stimulatory signal of CD40L/CD40,this interaction induces an inflammatory phenotype in monocytes,resulting in the secretion of inflammatory cytokines such as IL-1β,TNF-α,and IL-6.Furthermore,the spike protein-activated platelet-monocyte interaction promotes tissue factor expression on monocyte membranes and facilitates its release through microvesicles formation.In summary,our research reveals that SARS-CoV-2 spike protein directly interacts with and activates platelets via CD42 b,initiating platelet-monocyte crosstalk.Activated platelets,through P-selectin and CD40 L expression,activate monocytes,leading to the secretion of inflammatory cytokines and tissue factor release.This mechanism can explain the inflammation and coagulation abnormalities in severe COVID-19 patients and enhances our understanding of infection-related thrombotic pathology.This study first discovered that CD42 b serves as the receptor for SARS-CoV-2 activation of platelets,providing a more targeted point for antiplatelet therapy in COVID-19-related thrombosis.