This study is the first to reveal that SARS-CoV-2 infection induces CD147 upregulation through activation of the transcription factor AHR, thereby promoting persistent viral infection and immune imbalance. Furthermore, it resolves the cryo-EM structure of the CD147–spike complex, providing a direct structural basis for the therapeutic mechanism of the anti-CD147 antibody Meplazumab.
Literature Overview
The article titled 'Inducible CD147 up-regulation boosts extended SARS-CoV-2 infection triggering severe COVID-19 independent of ACE2,' published in Signal Transduction and Targeted Therapy, reviews and summarizes the molecular mechanisms by which SARS-CoV-2 infection promotes persistent infection and triggers severe pneumonia through upregulation of the host cell surface receptor CD147. The study finds that while SARS-CoV-2 infection downregulates the ACE2 receptor, it simultaneously upregulates CD147 expression via activation of the aryl hydrocarbon receptor (AHR) pathway, enhancing host cell susceptibility to the virus, enabling sustained viral replication in lung tissue, and causing severe pathological damage. Moreover, the study confirms that the anti-CD147 antibody Meplazumab effectively inhibits viral entry, reduces inflammatory cytokine levels, and restores immune balance. Finally, the authors resolved the structure of the CD147–spike complex using cryo-EM, identifying key amino acid residues involved in their interaction, thereby providing high-resolution structural evidence for CD147-targeted therapeutic strategies. This work systematically elucidates the central role of CD147-mediated, ACE2-independent infection pathways in severe COVID-19, expanding our understanding of viral pathogenesis.Background Knowledge
Severe COVID-19 is characterized by high viral load, persistent pulmonary inflammation, and immune dysregulation, leading to high mortality. SARS-CoV-2 is widely recognized to primarily enter cells via the ACE2 receptor. However, ACE2 is often downregulated post-infection due to ADAM17-mediated shedding, making it difficult to explain persistent infection. Thus, identifying alternative, ACE2-independent receptors has become a research hotspot. CD147 (Basigin/EMMPRIN), a transmembrane glycoprotein, plays roles in inflammatory responses, tumor progression, and viral infections. Previous studies have shown that CD147 can act as an attachment receptor for SARS-CoV-2, mediating viral entry through an Arf6-dependent endocytic pathway, particularly in cell types with low or absent ACE2 expression (e.g., T cells, astrocytes). However, how CD147 is regulated during infection, whether its expression is inducible, and whether it truly drives persistent infection and disease progression in vivo remain unclear due to a lack of direct evidence. Additionally, although the anti-CD147 antibody Meplazumab has shown therapeutic potential in clinical trials, its precise mechanism of action has not been structurally elucidated. Therefore, clarifying the dynamic regulatory mechanisms of CD147 during SARS-CoV-2 infection, validating its functional importance in animal models, and resolving the interaction interface between CD147 and the spike protein are crucial for understanding severe disease pathogenesis and developing targeted therapies. This study directly addresses these scientific questions, filling a critical gap in our understanding of CD147's role in SARS-CoV-2 infection.
Research Methods and Experiments
The study employed rhesus macaque and humanized hCD147 mouse models, establishing a COVID-19 infection model via intratracheal inoculation with the SARS-CoV-2 Beta variant to evaluate the therapeutic efficacy of the anti-CD147 antibody Meplazumab (MPZ) and the anti-ACE2 antibody (3E8). Viral load was measured by qRT-PCR, tissue pathology assessed via H&E staining and electron microscopy, and immune cell changes analyzed using multiplex immunofluorescence and scRNA-seq. CD147 and ACE2 expression levels were detected at both transcriptional and protein levels using scRNA-seq, spatial transcriptomics, and Western blot. The regulatory mechanism of CD147 was verified using AHR agonists/antagonists, AHR overexpression or knockdown experiments, dual-luciferase reporter assays, and nucleocytoplasmic fractionation. The interaction between CD147 and the spike protein was analyzed by surface plasmon resonance (SPR) and cryo-EM to resolve the complex structure, with key binding residues validated through mutagenesis experiments. Functional validation included pseudovirus and live virus infection assays, as well as cell-cell communication analysis using CellChat.Key Conclusions and Perspectives
Research Significance and Prospects
This study is the first to systematically reveal, at both in vivo and molecular levels, the inducibility of CD147 during SARS-CoV-2 infection and its central role in driving severe COVID-19, proposing a novel pathogenic axis of 'AHR–CD147–persistent viral infection–immune imbalance.' It provides a mechanistic explanation for the persistence of high viral loads despite ACE2 downregulation.
Structural biology data offer a precise molecular blueprint for designing anti-CD147 antibodies or small-molecule drugs. Notably, the five identified key residue pairs can serve as mutation surveillance sites to assess new variants’ dependence on the CD147 pathway. Moreover, the multifaceted effects of Meplazumab—antiviral, anti-inflammatory, and immune-restorative—make it a promising candidate for treating severe COVID-19, particularly in high-risk populations with low ACE2 expression or immune deficiencies.
Future studies could further explore the sources of AHR ligands during infection (e.g., tryptophan metabolites), evaluate the applicability of targeting the AHR–CD147 axis in other coronaviruses or RNA viruses, and advance Meplazumab into multicenter phase III clinical trials. Additionally, developing bispecific antibodies (e.g., targeting both CD147 and ACE2) or combination therapies may further enhance antiviral efficacy, offering new strategies for future pandemics.
Conclusion
This study systematically elucidates the molecular mechanism by which SARS-CoV-2 activates the host transcription factor AHR to induce CD147 upregulation, thereby bypassing the limitations imposed by ACE2 downregulation to achieve persistent infection and trigger severe pneumonia. By utilizing rhesus macaque and humanized mouse models combined with multi-omics technologies—including single-cell sequencing, spatial transcriptomics, and cryo-EM—the study provides direct evidence for CD147 as a functional receptor for SARS-CoV-2. Notably, the resolved structure of the CD147–spike complex reveals the critical amino acid interface involved in their interaction, offering a structural basis for the mechanism of action of the anti-CD147 antibody Meplazumab. Functionally, Meplazumab not only inhibits viral entry but also mitigates inflammation and restores immune balance, demonstrating multifaceted therapeutic potential. This work not only deepens our understanding of the pathogenesis of severe COVID-19 but also provides solid theoretical and experimental foundations for developing novel antiviral strategies targeting CD147, holding significant translational medical value. Future efforts should focus on advancing this pathway into clinical applications and exploring its broader relevance in other viral infections.
