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Close relatives of MERS-CoV in bats use ACE2 as their functional receptors

Author

Listed:
  • Qing Xiong

    (Wuhan University)

  • Lei Cao

    (Chinese Academy of Sciences)

  • Chengbao Ma

    (Wuhan University)

  • M. Alejandra Tortorici

    (University of Washington)

  • Chen Liu

    (Wuhan University)

  • Junyu Si

    (Wuhan University)

  • Peng Liu

    (Wuhan University)

  • Mengxue Gu

    (Wuhan University)

  • Alexandra C. Walls

    (University of Washington
    Howard Hughes Medical Institute)

  • Chunli Wang

    (Wuhan University)

  • Lulu Shi

    (Wuhan University)

  • Fei Tong

    (Wuhan University)

  • Meiling Huang

    (Wuhan University)

  • Jing Li

    (Wuhan University)

  • Chufeng Zhao

    (Wuhan University)

  • Chao Shen

    (Wuhan University)

  • Yu Chen

    (Wuhan University)

  • Huabin Zhao

    (Wuhan University)

  • Ke Lan

    (Wuhan University)

  • Davide Corti

    (Humabs BioMed SA, subsidiary of Vir Biotechnology)

  • David Veesler

    (University of Washington
    Howard Hughes Medical Institute)

  • Xiangxi Wang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Huan Yan

    (Wuhan University)

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) and several bat coronaviruses use dipeptidyl peptidase-4 (DPP4) as an entry receptor1–4. However, the receptor for NeoCoV—the closest known MERS-CoV relative found in bats—remains unclear5. Here, using a pseudotype virus entry assay, we found that NeoCoV and its close relative, PDF-2180, can efficiently bind to and use specific bat angiotensin-converting enzyme 2 (ACE2) orthologues and, less favourably, human ACE2 as entry receptors through their receptor-binding domains (RBDs) on the spike (S) proteins. Cryo-electron microscopy analysis revealed an RBD–ACE2 binding interface involving protein–glycan interactions, distinct from those of other known ACE2-using coronaviruses. We identified residues 337–342 of human ACE2 as a molecular determinant restricting NeoCoV entry, whereas a NeoCoV S pseudotyped virus containing a T510F RBD mutation efficiently entered cells expressing human ACE2. Although polyclonal SARS-CoV-2 antibodies or MERS-CoV RBD-specific nanobodies did not cross-neutralize NeoCoV or PDF-2180, an ACE2-specific antibody and two broadly neutralizing betacoronavirus antibodies efficiently inhibited these two pseudotyped viruses. We describe MERS-CoV-related viruses that use ACE2 as an entry receptor, underscoring a promiscuity of receptor use and a potential zoonotic threat.

Suggested Citation

  • Qing Xiong & Lei Cao & Chengbao Ma & M. Alejandra Tortorici & Chen Liu & Junyu Si & Peng Liu & Mengxue Gu & Alexandra C. Walls & Chunli Wang & Lulu Shi & Fei Tong & Meiling Huang & Jing Li & Chufeng Z, 2022. "Close relatives of MERS-CoV in bats use ACE2 as their functional receptors," Nature, Nature, vol. 612(7941), pages 748-757, December.
  • Handle: RePEc:nat:nature:v:612:y:2022:i:7941:d:10.1038_s41586-022-05513-3
    DOI: 10.1038/s41586-022-05513-3
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    Citations

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    Cited by:

    1. Jun-Yu Si & Yuan-Mei Chen & Ye-Hui Sun & Meng-Xue Gu & Mei-Ling Huang & Lu-Lu Shi & Xiao Yu & Xiao Yang & Qing Xiong & Cheng-Bao Ma & Peng Liu & Zheng-Li Shi & Huan Yan, 2024. "Sarbecovirus RBD indels and specific residues dictating multi-species ACE2 adaptiveness," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Anna S. Speranskaya & Ilia V. Artiushin & Andrei E. Samoilov & Elena V. Korneenko & Kirill V. Khabudaev & Elena N. Ilina & Alexander P. Yusefovich & Marina V. Safonova & Anna S. Dolgova & Anna S. Glad, 2023. "Identification and Genetic Characterization of MERS-Related Coronavirus Isolated from Nathusius’ Pipistrelle ( Pipistrellus nathusii ) near Zvenigorod (Moscow Region, Russia)," IJERPH, MDPI, vol. 20(4), pages 1-16, February.
    3. Ankita Leekha & Arash Saeedi & K M Samiur Rahman Sefat & Monish Kumar & Melisa Martinez-Paniagua & Adrian Damian & Rohan Kulkarni & Kate Reichel & Ali Rezvan & Shalaleh Masoumi & Xinli Liu & Laurence , 2024. "Multi-antigen intranasal vaccine protects against challenge with sarbecoviruses and prevents transmission in hamsters," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    4. Luo-Yuan Xia & Zhen-Fei Wang & Xiao-Ming Cui & Yuan-Guo Li & Run-Ze Ye & Dai-Yun Zhu & Fang-Xu Li & Jie Zhang & Wen-Hao Wang & Ming-Zhu Zhang & Wan-Ying Gao & Lian-Feng Li & Teng-Cheng Que & Tie-Cheng, 2024. "Isolation and characterization of a pangolin-borne HKU4-related coronavirus that potentially infects human-DPP4-transgenic mice," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    5. Matthew Gagne & Barbara J. Flynn & Christopher Cole Honeycutt & Dillon R. Flebbe & Shayne F. Andrew & Samantha J. Provost & Lauren McCormick & Alex Ry & Elizabeth McCarthy & John-Paul M. Todd & Saran , 2024. "Variant-proof high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Xuanxiu Ren & Jiawen Sun & Wenhua Kuang & Feiyang Yu & Bingjie Wang & Yong Wang & Wei Deng & Zhao Xu & Shangyu Yang & Hualin Wang & Yangbo Hu & Zengqin Deng & Yun-Jia Ning & Haiyan Zhao, 2024. "A broadly protective antibody targeting glycoprotein Gn inhibits severe fever with thrombocytopenia syndrome virus infection," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    7. Yingdan Wang & Aihua Hao & Ping Ji & Yunping Ma & Zhaoyong Zhang & Jiali Chen & Qiyu Mao & Xinyi Xiong & Palizhati Rehati & Yajie Wang & Yanqun Wang & Yumei Wen & Lu Lu & Zhenguo Chen & Jincun Zhao & , 2024. "A bispecific antibody exhibits broad neutralization against SARS-CoV-2 Omicron variants XBB.1.16, BQ.1.1 and sarbecoviruses," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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