Soluble SARS-CoV-2 Spike glycoprotein: considering some potential pathogenic effects

Bruno Azzarone^*Nadine LandolinaFrancesca Romana MariottiLORENZO MORETTAEnrico Maggi

• Tumor Immunology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

Soluble S1 subunit of Spike protein (SP) from the SARS-CoV2 of different variants of concern (VOC) may directly bind and activate human NK cells in vitro through the engagement of the toll-like receptor (TLR) 2 and TLR4. This mechanism revealed a novel pathogenic role played by NK cells not only in the different phases of disease, but also in the post-acute sequalae of COVID-19 (PASC) and in some postvaccination side effects.In addition to their binding to angiotensin converting enzyme (ACE2), which mediates virus attachment and cell entry, soluble SP triggers several active receptors/molecules expressed by many cells, inducing, in turn, the type I/III interferon decrease, the altered autophagy and apoptosis, the release of inflammatory cytokines and chemokines, the complement activation and endothelial damage which favour clotting events.In this review, we discuss the hypothesis that circulating SP, exerting multiple biological activities, can explain the heterogeneity of clinical outcomes of severe COVID-19, PASC and post-vaccine-related effects.Recent reports have clearly indicated that soluble SARS-CoV-2-and post vaccinal SP trigger the same cascade of events acting on immune response and promoting defined adverse events. Factors hindering the pathological activity of soluble SP are the SP plasma levels, the age of the infected/vaccinated people, the efficiency of protein synthesis of ectopic targets triggered by soluble SP, as well as the specificity, the titre and the affinity of anti-SP antibodies elicited by the infection. At the present, the ratio risk /benefit is largely in favour of vaccination: however, the excessive and persistent ectopic production of synthetic SP should be systematically analysed. This would allow to identify subjects at risk for major adverse events and to answer the urgent needs of efficient vaccines providing long-lasting activity with poor side effects.