Inducible CD147 up-regulation boosts persistent SARS-CoV-2 infection triggering severe COVID-19 independent of ACE2 [scRNA-seq]

The high mortality caused by severe COVID-19 poses challenges to public health. However, the pathogenesis of severe cases remains a puzzle. Here, we find that SARS-CoV-2 infection boosts CD147 inducible up-regulation, causing persistent virus infection and severe pathological lesions. Specifically, inducible expression of CD147 is transcriptionally regulated by the aryl hydrocarbon receptor (AHR) upon virus infection, while membrane-bound ACE2 decreases, thus indicating that CD147 is a predominant receptor responsible for persistent virus infection. Meanwhile, SARS-CoV-2 infection triggers immune imbalance by promoting cell death of CD4+ T and B cells and abnormal cell communications in rhesus macaque model. Meplazumab, a humanized CD147 antibody, effectively inhibits virus entry and cytokine level, and restores immune balance. We further resolve the cryo-EM structure of CD147-spike complex, and validate five pairs of residues at the interaction interface, which is blocked by Meplazumab via steric hindrance effect. Our findings uncover the pathogenesis of severe COVID-19.