2. Academic Validation
  3. APOE interacts with ACE2 inhibiting SARS-CoV-2 cellular entry and inflammation in COVID-19 patients

APOE interacts with ACE2 inhibiting SARS-CoV-2 cellular entry and inflammation in COVID-19 patients

  • Signal Transduct Target Ther. 2022 Aug 1;7(1):261. doi: 10.1038/s41392-022-01118-4.
Hongsheng Zhang  # 1 2,  Lin Shao  # 3,  Zhihao Lin  # 3,  Quan-Xin Long  # 4,  Huilong Yuan  # 3,  Lujian Cai 3,  Guangtong Jiang 3,  Xiaoyi Guo 3,  Renzhi Yang 2,  Zepeng Zhang 1,  Bingchang Zhang 1,  Fan Liu 1,  Zhiyong Li 1,  Qilin Ma 1,  Yun-Wu Zhang 1 3,  Ai-Long Huang 5,  Zhanxiang Wang 6,  Yingjun Zhao 7 8,  Huaxi Xu 9 10
Affiliations

Affiliations

  • 1 Center for Brain Sciences, the First Affiliated Hospital of Xiamen University, Institute of Neuroscience, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Xiamen University, Xiamen, China.
  • 2 Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, China.
  • 3 School of Medicine, Xiamen University, Xiamen, China.
  • 4 Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, China.
  • 5 Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, China. ahuang@cqmu.edu.cn.
  • 6 Center for Brain Sciences, the First Affiliated Hospital of Xiamen University, Institute of Neuroscience, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Xiamen University, Xiamen, China. wangzx@xmu.edu.cn.
  • 7 Center for Brain Sciences, the First Affiliated Hospital of Xiamen University, Institute of Neuroscience, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Xiamen University, Xiamen, China. yjzhao@xmu.edu.cn.
  • 8 School of Medicine, Xiamen University, Xiamen, China. yjzhao@xmu.edu.cn.
  • 9 Center for Brain Sciences, the First Affiliated Hospital of Xiamen University, Institute of Neuroscience, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Xiamen University, Xiamen, China. hxxu@xmu.edu.cn.
  • 10 Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, China. hxxu@xmu.edu.cn.
  • # Contributed equally.
PMID: 35915083 DOI: 10.1038/s41392-022-01118-4
Abstract

Apolipoprotein E (APOE) plays a pivotal role in lipid including Cholesterol metabolism. The APOE ε4 (APOE4) allele is a major genetic risk factor for Alzheimer's and cardiovascular diseases. Although APOE has recently been associated with increased susceptibility to infections of several viruses, whether and how APOE and its isoforms affect SARS-CoV-2 Infection remains unclear. Here, we show that serum concentrations of APOE correlate inversely with levels of cytokine/chemokine in 73 COVID-19 patients. Utilizing multiple protein interaction assays, we demonstrate that APOE3 and APOE4 interact with the SARS-CoV-2 receptor ACE2; and APOE/ACE2 interactions require zinc metallopeptidase domain of ACE2, a key docking site for SARS-CoV-2 Spike protein. In addition, immuno-imaging assays using confocal, super-resolution, and transmission electron microscopies reveal that both APOE3 and APOE4 reduce ACE2/Spike-mediated viral entry into cells. Interestingly, while having a comparable binding affinity to ACE2, APOE4 inhibits viral entry to a lesser extent compared to APOE3, which is likely due to APOE4's more compact structure and smaller spatial obstacle to compete against Spike binding to ACE2. Furthermore, APOE ε4 carriers clinically correlate with increased SARS-CoV-2 Infection and elevated serum inflammatory factors in 142 COVID-19 patients assessed. Our study suggests a regulatory mechanism underlying SARS-CoV-2 Infection through APOE interactions with ACE2, which may explain in part increased COVID-19 Infection and disease severity in APOE ε4 carriers.

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