Primate-specific BTN3A2 protects against SARS-CoV-2 infection by interacting with and reducing ACE2Research in context
Ling Xu,
Dandan Yu,
Min Xu,
Yamin Liu,
Lu-Xiu Yang,
Qing-Cui Zou,
Xiao-Li Feng,
Ming-Hua Li,
Nengyin Sheng,
Yong-Gang Yao
Affiliations
Ling Xu
Key Laboratory of Genetic Evolution and Animal Models, Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, and KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, China; Kunming National High-Level Biosafety Research Center for Non-Human Primates, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650107, China; Corresponding author. Key Laboratory of Genetic Evolution and Animal Models, Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, and KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, China.
Dandan Yu
Key Laboratory of Genetic Evolution and Animal Models, Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, and KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, China; Kunming National High-Level Biosafety Research Center for Non-Human Primates, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650107, China
Min Xu
Key Laboratory of Genetic Evolution and Animal Models, Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, and KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, China
Yamin Liu
Key Laboratory of Genetic Evolution and Animal Models, Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, and KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, China
Lu-Xiu Yang
Key Laboratory of Genetic Evolution and Animal Models, Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, and KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, China
Qing-Cui Zou
Kunming National High-Level Biosafety Research Center for Non-Human Primates, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650107, China
Xiao-Li Feng
Kunming National High-Level Biosafety Research Center for Non-Human Primates, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650107, China
Ming-Hua Li
Kunming National High-Level Biosafety Research Center for Non-Human Primates, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650107, China
Nengyin Sheng
Key Laboratory of Genetic Evolution and Animal Models, Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, and KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, China; Corresponding author. Key Laboratory of Genetic Evolution and Animal Models, Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, and KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, China.
Yong-Gang Yao
Key Laboratory of Genetic Evolution and Animal Models, Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, and KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, China; Kunming National High-Level Biosafety Research Center for Non-Human Primates, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650107, China; National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), National Resource Center for Non-Human Primates, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650107, China; Corresponding author. Key Laboratory of Genetic Evolution and Animal Models, Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, and KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, China.
Summary: Background: Coronavirus disease 2019 (COVID-19) is an immune-related disorder caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The complete pathogenesis of the virus remains to be determined. Unraveling the molecular mechanisms governing SARS-CoV-2 interactions with host cells is crucial for the formulation of effective prophylactic measures and the advancement of COVID-19 therapeutics. Methods: We analyzed human lung single-cell RNA sequencing dataset to discern the association of butyrophilin subfamily 3 member A2 (BTN3A2) expression with COVID-19. The BTN3A2 gene edited cell lines and transgenic mice were infected by live SARS-CoV-2 in a biosafety level 3 (BSL-3) laboratory. Immunoprecipitation, flow cytometry, biolayer interferometry and competition ELISA assays were performed in BTN3A2 gene edited cells. We performed quantitative real-time PCR, histological and/or immunohistochemical analyses for tissue samples from mice with or without SARS-CoV-2 infection. Findings: The BTN3A2 mRNA level was correlated with COVID-19 severity. BTN3A2 expression was predominantly identified in epithelial cells, elevated in pathological epithelial cells from COVID-19 patients and co-occurred with ACE2 expression in the same lung cell subtypes. BTN3A2 targeted the early stage of the viral life cycle by inhibiting SARS-CoV-2 attachment through interactions with the receptor-binding domain (RBD) of the Spike protein and ACE2. BTN3A2 inhibited ACE2-mediated SARS-CoV-2 infection by reducing ACE2 in vitro and in vivo. Interpretation: These results reveal a key role of BTN3A2 in the fight against COVID-19. Identifying potential monoclonal antibodies which mimic BTN3A2 may facilitate disruption of SARS-CoV-2 infection, providing a therapeutic avenue for COVID-19. Funding: This study was supported by the National Natural Science Foundation of China (32070569, U1902215, and 32371017), the CAS “Light of West China” Program, and Yunnan Province (202305AH340006).
