Azzarone Bruno, Landolina Nadine, Mariotti Francesca Romana, Moretta Lorenzo, Maggi Enrico
Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Front Immunol. 2025 Jun 4;16:1616106. doi: 10.3389/fimmu.2025.1616106. eCollection 2025.
The soluble S1 subunit of Spike protein (SP) from the SARS-CoV-2 of different variants of concern (VOCs) may directly bind and activate human NK cells 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 sequelae of COVID-19 (PASC) and some post-vaccination side effects. In addition to its binding to angiotensin-converting enzyme 2 (ACE2), which mediates virus attachment and cell entry, soluble SP triggers several active receptors/molecules expressed by many cells, inducing, in turn, type I/III interferon decrease, altered autophagy and apoptosis, the release of inflammatory cytokines and chemokines, 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 the clinical outcomes of severe COVID-19, PASC and post-vaccine-related effects. Recent reports have clearly indicated that soluble SARS-CoV-2 and post-vaccination SP trigger the same cascade of events, acting on the 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 and 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 present, the risk/benefit ratio is largely in favour of vaccination; however, the excessive and persistent ectopic production of synthetic SP should be systematically analysed. This would allow for the identification of subjects at risk for major adverse events and to answer the urgent need for efficient vaccines that provide long-lasting activity with minimal side effects.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）不同变异株的刺突蛋白（SP）可溶性S1亚基可通过与Toll样受体（TLR）2和TLR4结合，直接结合并激活人类自然杀伤（NK）细胞。这一机制揭示了NK细胞不仅在疾病的不同阶段，而且在新冠后遗症（PASC）和一些疫苗接种后副作用中发挥的新致病作用。除了与介导病毒附着和细胞进入的血管紧张素转换酶2（ACE2）结合外，可溶性SP还能触发许多细胞表达的多种活性受体/分子，进而导致I/III型干扰素减少、自噬和凋亡改变、炎性细胞因子和趋化因子释放、补体激活以及内皮损伤，这些都有利于凝血事件的发生。在本综述中，我们讨论了一种假说，即循环中的SP发挥多种生物学活性，可以解释重症COVID-19、PASC和疫苗接种后相关效应临床结果的异质性。最近的报告清楚地表明，可溶性SARS-CoV-2和疫苗接种后的SP触发相同的事件级联，作用于免疫反应并促进特定不良事件的发生。阻碍可溶性SP病理活性的因素包括SP血浆水平、感染/接种疫苗者的年龄、可溶性SP触发的异位靶点的蛋白质合成效率，以及感染引发的抗SP抗体的特异性、滴度和亲和力。目前，风险/收益比在很大程度上有利于接种疫苗；然而，合成SP的过度和持续异位产生应进行系统分析。这将有助于识别有发生重大不良事件风险的个体，并满足对高效、副作用最小且具有持久活性的疫苗的迫切需求。
