# Inducible CD147 up-regulation boosts extended SARS-CoV-2 infection triggering severe COVID-19 independent of ACE2

## TL;DR

This study shows that CD147 up-regulation during SARS-CoV-2 infection worsens severe COVID-19 by extending viral spread and causing immune imbalance.

## Contribution

The study reveals CD147 as a novel target for severe COVID-19 and presents a cryo-EM structure of the CD147-spike complex.

## Key findings

- SARS-CoV-2 infection increases CD147 in lung tissues of rhesus macaques, leading to extended infection and severe lesions.
- Meplazumab, an anti-CD147 antibody, inhibits virus entry and restores immune balance in infected models.
- Cryo-EM structure of CD147-spike complex identifies functional residues disrupted by Meplazumab.

## Abstract

The high mortality caused by severe COVID-19 poses great challenges to the public health. However, the underlying pathogenesis of severe cases remains unclear. Here, we find that SARS-CoV-2 infection boosts CD147 inducible up-regulation in the lung tissues of virus-infected rhesus macaques coupled with down-regulated membrane-bound ACE2, which conduces to extended virus infection and severe pathological lesions. Specifically, SARS-CoV-2 infection enhances the expression of transcriptional factor aryl hydrocarbon receptor and facilitates its nucleus translocation, which causes CD147 gene transcription and its up-regulation in protein level, thereby leading to virus susceptibility of the hosts and extended virus infection. Meanwhile, SARS-CoV-2 infection triggers immune imbalance of lung tissues by promoting cell death of CD4 + T cells and B cells and mediating abnormal cell-cell communications, especially for M2 macrophages. Meplazumab, a humanized anti-CD147 antibody, effectively inhibits virus entry and cytokine level, and restores immune balance in the lung tissues of virus-infected rhesus macaque model. Importantly, we further present the cryo-EM structure of CD147-spike complex, and identify five pairs of functional residues for their interaction, which could be interrupted by Meplazumab via steric hindrance effect. Our findings provide direct evidence for CD147-SARS-CoV-2 spike interaction and uncover the pathogenesis of severe COVID-19 caused by CD147-mediated extended virus infection.