SARS-CoV-2 mutations contribute to increased viral transmissibility and immune escape, compromising the effectiveness of existing vaccines and neutralizing antibodies. An in-depth investigation on COVID-19 pathogenesis is urgently needed to develop a strategy against SARS-CoV-2 variants. Here, we identified CD147 as a universal receptor for SARS-CoV-2 and its variants. Meanwhile, Meplazeumab, a humanized anti-CD147 antibody, could block cellular entry of SARS-CoV-2 and its variants—alpha, beta, gamma, and delta, with inhibition rates of 68.7, 75.7, 52.1, 52.1, and 62.3% at 60 μg/ml, respectively. Furthermore, humanized CD147 transgenic mice were susceptible to SARS-CoV-2 and its two variants, alpha and beta. When infected, these mice developed exudative alveolar pneumonia, featured by immune responses involving alveoli-infiltrated macrophages, neutrophils, and lymphocytes and activation of IL-17 signaling pathway. Mechanistically, we proposed that severe COVID-19-related cytokine storm is induced by a “spike protein-CD147-CyPA signaling axis”: Infection of SARS-CoV-2 through CD147 initiated the JAK-STAT pathway, which further induced expression of cyclophilin A (CyPA); CyPA reciprocally bound to CD147 and triggered MAPK pathway. Consequently, the MAPK pathway regulated the expression of cytokines and chemokines, which promoted the development of cytokine storm. Importantly, Meplazumab could effectively inhibit viral entry and inflammation caused by SARS-CoV-2 and its variants. Therefore, our findings provided a new perspective for severe COVID-19-related pathogenesis. Furthermore, the validated universal receptor for SARS-CoV-2 and its variants can be targeted for COVID-19 treatment.

SARS-CoV-2 突变会增加病毒传播性和免疫逃逸，从而损害现有疫苗和中和抗体的有效性。迫切需要对 COVID-19 发病机制进行深入研究，以制定针对 SARS-CoV-2 变种的策略。在这里，我们确定 CD147 是 SARS-CoV-2 及其变体的通用受体。同时，Meplazeumab 是一种人源化抗 CD147 抗体，可以阻断 SARS-CoV-2 及其变体（α、β、γ 和 δ）进入细胞，抑制率分别为 68.7%、75.7%、52.1%、52.1% 和 62.3%。分别为60微克/毫升。此外，人源化 CD147 转基因小鼠对 SARS-CoV-2 及其两种变体 α 和 β 敏感。当感染时，这些小鼠出现渗出性肺泡肺炎，其特征是涉及肺泡浸润的巨噬细胞、中性粒细胞和淋巴细胞的免疫反应以及IL-17信号通路的激活。从机制上讲，我们提出与COVID-19相关的严重细胞因子风暴是由“刺突蛋白-CD147-CyPA信号轴”引起的：通过CD147感染SARS-CoV-2启动了JAK-STAT通路，进一步诱导了亲环蛋白的表达A (CyPA); CyPA 与 CD147 相互结合并触发 MAPK 通路。因此，MAPK通路调节细胞因子和趋化因子的表达，促进细胞因子风暴的发生。重要的是，Meplazumab 可以有效抑制 SARS-CoV-2 及其变种引起的病毒进入和炎症。因此，我们的研究结果为与 COVID-19 相关的重症发病机制提供了新的视角。此外，经过验证的 SARS-CoV-2 及其变体通用受体可以作为 COVID-19 治疗的目标。