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Structural insight reveals SARS-CoV-2 ORF7a as an immunomodulating factor for human CD14+ monocytes
Ziliang Zhou1, Chunliu Huang2, Zhechong Zhou1
1Molecular Imaging Center, Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
Abstract:
Dysregulated immune cell responses have been linked to the severity of coronavirus disease 2019 (COVID-19), but the specific viral factors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were currently unknown. Herein, we reveal that the Immunoglobulin-like fold ectodomain of the viral protein SARS-CoV-2 ORF7a interacts with high efficiency to CD14+ monocytes in human peripheral blood, compared to pathogenic protein SARS-CoV ORF7a. The crystal structure of SARS-CoV-2 ORF7a at 2.2 Å resolution reveals three remarkable changes on the amphipathic side of the four-stranded β-sheet, implying a potential functional interface of the viral protein. Importantly, SARS-CoV-2 ORF7a coincubation with CD14+ monocytes ex vivo triggered a decrease in HLA-DR/DP/DQ expression levels and upregulated significant production of proinflammatory cytokines, including IL-6, IL-1β, IL-8, and TNF-α. Our work demonstrates that SARS-CoV-2 ORF7a is an immunomodulating factor for immune cell binding and triggers dramatic inflammatory responses, providing promising therapeutic drug targets for pandemic COVID-19.
Insights
The SARS-CoV-2 ORF7a protein binds to monocytes, triggering inflammation and decreasing immune markers. This viral protein is a potential therapeutic target for COVID-19.
Area of Science:
- Immunology
- Virology
- Structural Biology
Background:
- Immune cell dysregulation correlates with COVID-19 severity.
- Specific SARS-CoV-2 viral factors influencing immune responses remain largely unidentified.
Purpose of the Study:
- To investigate the interaction of SARS-CoV-2 ORF7a with immune cells.
- To elucidate the structural basis of SARS-CoV-2 ORF7a's interaction with monocytes.
- To determine the immunomodulatory effects of SARS-CoV-2 ORF7a on human monocytes.
Main Methods:
- Crystallography was used to determine the structure of SARS-CoV-2 ORF7a.
- Interaction efficiency of SARS-CoV-2 ORF7a with CD14+ monocytes was assessed.
- Ex vivo experiments evaluated the impact of SARS-CoV-2 ORF7a on monocyte HLA-DR/DP/DQ expression and cytokine production.
Main Results:
- SARS-CoV-2 ORF7a exhibits high-efficiency binding to CD14+ monocytes.
- The crystal structure revealed potential functional interfaces on SARS-CoV-2 ORF7a.
- SARS-CoV-2 ORF7a decreased HLA-DR/DP/DQ expression and increased pro-inflammatory cytokines (IL-6, IL-1β, IL-8, TNF-α) in monocytes.
Conclusions:
- SARS-CoV-2 ORF7a acts as an immunomodulatory protein, influencing immune cell binding and inflammatory responses.
- The findings highlight SARS-CoV-2 ORF7a as a potential therapeutic target for managing COVID-19-associated inflammation.
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