Journal
ISCIENCE
Volume 24, Issue 3, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.isci.2021.102187
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Funding
- National Key R&D Program of China [2019YFA0110300, 2020YFA0509400]
- Special Fund for Scientific and Technological Innovation Strategy of Guangdong Province of China [2018B030306029]
- COVID-19 Emerging Prevention Products, Research Special Fund of Zhuhai City [ZH22036302200016PWC]
- National Natural Science Foundation of China [82071745]
- Fundamental Research Funds for the Central Universities [19ykzd36]
- Science and Technology Program of Guangzhou [202002030069]
- MOE Key Laboratory of Gene Function and Regulation
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SARS-CoV-2 ORF7a interacts efficiently with human CD14(+) monocytes, triggering inflammatory responses such as decreased HLA expression and increased production of proinflammatory cytokines. This suggests that ORF7a may be a key immunomodulating factor in the severe immune response seen in COVID-19 patients.
Dysregulated immune cell responses have been linked to the severity of corona-virus 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 angstrom resolution reveals three remarkable changes on the amphipathic side of the four-stranded beta-sheet, implying a potential functional interface of the viral protein. Importantly, SARS-CoV-2 ORF7a co-incubation 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-1 beta, IL-8, and TNF-alpha. 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.
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