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

ABSTRACT: 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.

ORGANISM(S): Mus musculus Macaca mulatta

PROVIDER: GSE298098 | GEO | 2025/12/02

REPOSITORIES: GEO

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Project description:Objectives: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes the worldwide COVID-19 pandemic. While SARS-CoV-2 can infect people of all ages and both sexes, senior populations are at greatest risk of severe disease and worse outcomes, and sexual dimorphism has been reported in COVID-19. COVID-19 causes damage to multiple organ systems, including the brain. Neurological symptoms are widely observed in patients with Covid-19, with many survivors suffering from persistent neurological impairment, potentially accelerating Alzheimer’s disease (AD). This study aims to investigate the mechanisms underlying the impact of age, and sex on neuroinflammation due to SARS-CoV-2 infection using mouse models. Methods: Wild-type C57BL/6 mice were subjected to intranasal inoculation of SARS-CoV-2 lineage B.1.351, followed by daily body weight monitoring. At 7 dpi, viral burden and inflammatory cytokine/chemokine responses in the lung and brain were determined by quantitative RT-PCR, followed by immunohistochemical and transcriptomic analyses. Results: Older age, male sex, showed increased lung viral loads and severity of SARS-CoV-2 infection in mice. No viral RNA was detected in the brains of infected mice; however, IL-6 and CCL2 mRNA increased significantly, particularly in brains of old and APOE4 mice. Unbiased brain RNA-seq/transcriptomic analysis showed that SARS-CoV-2 infection caused significant changes in gene expression profiles, and pathway analysis identified innate immunity and defense response to virus and other organisms as the major molecular networks affected in the brain by SARS-CoV-2 infection. Conclusions: Our findings demonstrate that age, and sex, modify the progression and outcome of SARS-CoV-2 infection. SARS-CoV-2 infection triggers neuroinflammatory responses despite the lack of detectable virus in the brain. Changes in molecular networks of innate immunity and defense response to microorganisms underlie the impact of SARS-CoV-2 infection in the brain. These findings in mice mimic epidemiological and clinical observations in humans with Covid-19.

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

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