AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells

  • Cell Res. 2021 Feb;31(2):126-140. doi: 10.1038/s41422-020-00460-y.
Shuai Wang   #  1  2  3 ,  Zongyang Qiu   #  1  2  3 ,  Yingnan Hou   #  1  2  3 ,  Xiya Deng   #  1  2  3 ,  Wei Xu   #  4 ,  Tingting Zheng  1  2  3 ,  Peihan Wu  1  2  3 ,  Shaofang Xie  1  2  3 ,  Weixiang Bian  1  2  3 ,  Chong Zhang  5 ,  Zewei Sun  5 ,  Kunpeng Liu  6 ,  Chao Shan  6 ,  Aifu Lin  7 ,  Shibo Jiang  4 ,  Youhua Xie  4 ,  Qiang Zhou  1  2  3 ,  Lu Lu  8 ,  Jing Huang  9  10  11 ,  Xu Li  12  13  14
Affiliations
  • 1. Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, 310024, China.
  • 2. Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, 310024, China.
  • 3. Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, 310024, China.
  • 4. Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences and Biosafety Level 3 Laboratory, Fudan University, Shanghai, 200032, China.
  • 5. The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China.
  • 6. Center for Biosafety Mega-Science, Wuhan Institute of Virology, State Key Laboratory of Virology, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China.
  • 7. Key Laboratory for Cell and Gene Engineering of Zhejiang Province, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 8. Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences and Biosafety Level 3 Laboratory, Fudan University, Shanghai, 200032, China. [email protected].
  • 9. Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, 310024, China. [email protected].
  • 10. Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, 310024, China. [email protected].
  • 11. Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, 310024, China. [email protected].
  • 12. Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, 310024, China. [email protected].
  • 13. Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, 310024, China. [email protected].
  • 14. Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, 310024, China. [email protected].
  • # Contributed equally.
PMID: 33420426 DOI: 10.1038/s41422-020-00460-y
Abstract

The current coronavirus disease 2019 (COVID-19) pandemic presents a global public health challenge. The viral pathogen responsible, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), binds to the host receptor ACE2 through its spike (S) glycoprotein, which mediates membrane fusion and viral entry. Although the role of ACE2 as a receptor for SARS-CoV-2 is clear, studies have shown that ACE2 expression is extremely low in various human tissues, especially in the respiratory tract. Thus, other host receptors and/or co-receptors that promote the entry of SARS-CoV-2 into cells of the respiratory system may exist. In this study, we found that the tyrosine-protein kinase receptor UFO (Axl) specifically interacts with the N-terminal domain of SARS-CoV-2 S. Using both a SARS-CoV-2 virus pseudotype and authentic SARS-CoV-2, we found that overexpression of Axl in HEK293T cells promotes SARS-CoV-2 entry as efficiently as overexpression of ACE2, while knocking out Axl significantly reduces SARS-CoV-2 Infection in H1299 pulmonary cells and in human primary lung epithelial cells. Soluble human Recombinant AXL blocks SARS-CoV-2 Infection in cells expressing high levels of Axl. The Axl expression level is well correlated with SARS-CoV-2 S level in bronchoalveolar lavage fluid cells from COVID-19 patients. Taken together, our findings suggest that Axl is a novel candidate receptor for SARS-CoV-2 which may play an important role in promoting Viral Infection of the human respiratory system and indicate that it is a potential target for future clinical intervention strategies.

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