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Published on: November 5, 2021
SARS-CoV-2 enhances complement-mediated endothelial injury via the suppression of membrane complement regulatory
Jian Wu1,2, Sanpeng Xu3, Zhiqing Li2
1Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
Insights
Severe COVID-19 involves complement hyperactivation and thrombotic microangiopathy. SARS-CoV-2 proteins disrupt endothelial cell defenses against complement attack, revealing potential therapeutic targets.
Area of Science:
- Immunology
- Virology
- Pathology
Background:
- Severe COVID-19 is linked to complement system hyperactivation and thrombotic microangiopathy.
- Endothelial dysfunction is a critical factor in the development of thrombotic microangiopathy.
Purpose of the Study:
- To investigate how SARS-CoV-2 proteins affect endothelial cell sensitivity to complement-mediated damage.
- To elucidate the mechanisms linking endothelial injury, complement activation, and thrombotic microangiopathy in severe COVID-19.
Main Methods:
- CRISPR/Cas9-gRNA library screening to identify regulators of complement regulatory proteins (CRPs) on endothelial cells.
- Analysis of SARS-CoV-2 protein interactions with endothelial cells and complement components.
- Investigation of the role of interferons (IFN-γ, IFN-α) and cytokines (GM-CSF) in modulating endothelial cell protection.
Main Results:
- Multiple SARS-CoV-2 proteins (M, NSP16, ORF9b) were found to enhance complement-mediated cytotoxicity by inhibiting CRPs and promoting FCN1 deposition.
- ADAMTS9, SYAP1, and HIGD1A were identified as intrinsic regulators of CD59, targeted by SARS-CoV-2 proteins.
- IFN-γ, GM-CSF, and IFN-α upregulated CD55 and CD59; IFN-γ counteracted SARS-CoV-2 inhibition of CD59.
Conclusions:
- SARS-CoV-2 infection disrupts endothelial cell defense mechanisms against complement-mediated injury.
- Deficiency in IFN-γ may exacerbate complement-mediated endothelial damage during infection.
- Understanding these interactions provides insights into severe COVID-19 pathogenesis and potential therapeutic strategies targeting endothelial protection.
Abstract:
Complement hyperactivation and thrombotic microangiopathy are closely associated with severe COVID-19. Endothelial dysfunction is a key mechanism underlying thrombotic microangiopathy. To address the relationship between endothelial injury, complement activation and thrombotic microangiopathy of severe COVID-19, we wonder whether, and if so, what and how SARS-CoV-2 factors make endothelial cells (ECs) sensitive to complement-mediated cytotoxicity. We revealed that multiple SARS-CoV-2 proteins enhanced complement-mediated cytotoxicity to ECs by inhibiting membrane complement regulatory proteins (CRPs) and enhancing the deposition of complement-recognizing component FCN1. By screening with CRISPR/Cas9-gRNA libraries, we identified that ADAMTS9, SYAP1, and HIGD1A as intrinsic regulators of CD59 on ECs, which were inhibited by the SARS-CoV-2 M, NSP16, and ORF9b proteins. IFN-γ, GM-CSF, and IFN-α upregulated CD55 and CD59, while IFN-γ antagonized the inhibition of CD59 by the three SARS-CoV-2 proteins. So, the deficiency of IFN-γ weakened the protection of ECs by CRPs against complement-mediated injury which may be enhanced during infection. Our findings illustrated the regulation of protection against complement-mediated attack on self-cells by SARS-CoV-2 infection and immune responses, providing insights into endothelial injury, thrombotic microangiopathy, and potential targets for treating severe COVID-19.
