CD147 antibody specifically and effectively inhibits infection and cytokine storm of SARS-CoV-2 and its variants delta, alpha, beta, and gamma

Abstract

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.

The SARS-CoV-2 Spike protein disrupts human cardiac pericytes function through CD147 receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease

“…Supportive proof for the involvement of CD147 also came from research in vivo . In preclinical studies, transgenic expression of the human CD147 receptor conferred mice with an increased susceptibility to SARS-CoV-2 infection [ 48 ], while the administration of a neutralising antibody against the receptor successfully treated exudative pneumonia [ 48 ]. Importantly, these preclinical results were confirmed by an open-label clinical trial of meplazumab, a humanised therapeutic monoclonal antibody against CD147, which showed striking improvements in COVID-19 patients [ 26 ].…”

Significance of Immune Status of SARS-CoV-2 Infected Patients in Determining the Efficacy of Therapeutic Interventions

“…The CD147 is now revealed as a universal entry receptor for the SARS-CoV-2 viruses, including its predominant variants and signaling pathway initiator, particularly cytokine storms. CD147 antibody effectively and specifically inhibit infection and block cellular entry of SARS-CoV-2 viruses and also helps in alleviating cytokine storm for almost all variants, including alpha, delta, beta, and gamma [ 69 ]. CD147 antibody named meplazumab effectively inhibits the SARS-CoV-2 virus and reduces cytokine storm by blocking the direct interactions between S glycoprotein and CD147 [ 70 ].…”

The molecular mechanism of SARS-CoV-2 evading host antiviral innate immunity

“…Consequently, the MAPK pathway regulated the expression of cytokines and chemokines, which promoted the development of cytokine storms [ 57 ]. Thorne et al discovered that activating cytoplasmic RNA sensors RIG-I and MDA5 triggers a robust innate immune response when SARS-CoV-2 invades.…”