APOBEC3-related mutations in the spike protein-encoding region facilitate SARS-CoV-2 evolution
Jiaying Shen,
Xinxin Xu,
Junyan Fan,
Hongsen Chen,
Yue Zhao,
Weijin Huang,
Wenbin Liu,
Zihan Zhang,
Qianqian Cui,
Qianqian Li,
Zheyun Niu,
Dongming Jiang,
Guangwen Cao
Affiliations
Jiaying Shen
Tongji University School of Medicine, Tongji University, Shanghai 200120, China; Key Laboratory of Biological Defense, Ministry of Education, China; Shanghai Key Laboratory of Medical Bioprotection, China
Xinxin Xu
Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
Junyan Fan
Key Laboratory of Biological Defense, Ministry of Education, China; Shanghai Key Laboratory of Medical Bioprotection, China; Department of Epidemiology, Second Military Medical University, Shanghai, China
Hongsen Chen
Key Laboratory of Biological Defense, Ministry of Education, China; Shanghai Key Laboratory of Medical Bioprotection, China; Department of Epidemiology, Second Military Medical University, Shanghai, China
Yue Zhao
Key Laboratory of Biological Defense, Ministry of Education, China; Shanghai Key Laboratory of Medical Bioprotection, China; Department of Epidemiology, Second Military Medical University, Shanghai, China
Weijin Huang
Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), WHO Collaborating Center for Standardization and Evaluation of Biologicals, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products and NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, 102629 Beijing, China
Wenbin Liu
Key Laboratory of Biological Defense, Ministry of Education, China; Shanghai Key Laboratory of Medical Bioprotection, China; Department of Epidemiology, Second Military Medical University, Shanghai, China
Zihan Zhang
Tongji University School of Medicine, Tongji University, Shanghai 200120, China; Key Laboratory of Biological Defense, Ministry of Education, China; Shanghai Key Laboratory of Medical Bioprotection, China
Qianqian Cui
Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), WHO Collaborating Center for Standardization and Evaluation of Biologicals, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products and NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, 102629 Beijing, China
Qianqian Li
Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), WHO Collaborating Center for Standardization and Evaluation of Biologicals, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products and NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, 102629 Beijing, China
Zheyun Niu
Tongji University School of Medicine, Tongji University, Shanghai 200120, China; Key Laboratory of Biological Defense, Ministry of Education, China; Shanghai Key Laboratory of Medical Bioprotection, China
Dongming Jiang
Tongji University School of Medicine, Tongji University, Shanghai 200120, China; Key Laboratory of Biological Defense, Ministry of Education, China; Shanghai Key Laboratory of Medical Bioprotection, China
Guangwen Cao
Tongji University School of Medicine, Tongji University, Shanghai 200120, China; Key Laboratory of Biological Defense, Ministry of Education, China; Shanghai Key Laboratory of Medical Bioprotection, China; Department of Epidemiology, Second Military Medical University, Shanghai, China; Corresponding author. Department of Epidemiology, Second Military Medical University, Shanghai, China.
SARS-CoV-2 evolves gradually to cause COVID-19 epidemic. One of driving forces of SARS-CoV-2 evolution might be activation of apolipoprotein B mRNA editing catalytic subunit-like protein 3 (APOBEC3) by inflammatory factors. Here, we aimed to elucidate the effect of the APOBEC3-related viral mutations on the infectivity and immune evasion of SARS-CoV-2. The APOBEC3-related C > U mutations ranked as the second most common mutation types in the SARS-CoV-2 genome. mRNA expression of APOBEC3A (A3A), APOBEC3B (A3B), and APOBEC3G (A3G) in peripheral blood cells increased with disease severity. A3B, a critical member of the APOBEC3 family, was significantly upregulated in both severe and moderate COVID-19 patients and positively associated with neutrophil proportion and COVID-19 severity. We identified USP18 protein, a key molecule centralizing the protein-protein interaction network of key APOBEC3 proteins. Furthermore, mRNA expression of USP18 was significantly correlated to ACE2 and TMPRSS2 expression in the tissue of upper airways. Knockdown of USP18 mRNA significantly decreased A3B expression. Ectopic expression of A3B gene increased SARS-CoV-2 infectivity. C > U mutations at S371F, S373L, and S375F significantly conferred with the immune escape of SARS-CoV-2. Thus, APOBEC3, whose expression are upregulated by inflammatory factors, might promote SARS-CoV-2 evolution and spread via upregulating USP18 level and facilitating the immune escape. A3B and USP18 might be therapeutic targets for interfering with SARS-CoV-2 evolution.
