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. Overall design: The rhesus macaques (n=16) were challenged with 106 TCID50 SARS-CoV-2 (Beta strain) by intratracheal routes at 0 dpi and divided into four groups. At 1 dpi, the rhesus macaques were injected intravenously with MPZ or 3E8 antibody. The groups were listed as follows: Ctrl group (PBS), MPZ group (MPZ, 10 mg/kg), 3E8 group (3E8, 10 mg/kg), and MPZ+3E8 group (MPZ, 5 mg/kg; 3E8, 5 mg/kg). At 7 dpi, the rhesus macaques were euthanized to collect the lung tissues for scRNA-seq and spatial transcriptomics analysis. Meanwhile, the lung tissues from four healthy rhesus macaques were used as the control. The hCD147 mice (n=4) were also challenged with 105 TCID50 SARS-CoV-2 (Beta strain) intranasally at 0 dpi. At 3 dpi, the mice were euthanized to collect the lung tissues for scRNA-seq and spatial transcriptomics analysis.