Convergent use of aminopeptidase N receptor by hedgehog merbecoviruses
Abstract
Abstract Coronaviruses circulating in wildlife, such as European and Asian hedgehog merbecoviruses (EriCoVs), pose a potential transmission risk. Knowledge of viral receptors can inform risk assessment and development of countermeasures; however, the functional receptor for EriCoVs is unknown. Here we identify hedgehog aminopeptidase N (APN) as a functional receptor for various EriCoVs. Analysis of APN orthologues from 93 species reveals a restricted APN tropism for EriCoVs, primarily utilizing APN from hedgehogs and to a lesser extent felid APN. Cryogenic electron microscopy analysis of the EriCoV–APN complex reveals an APN-binding mode that is distinct from those used by alpha- and deltacoronaviruses. Functional assays suggest that proteolytic activation of EriCoV spikes can be facilitated by multiple proteases in a context- and strain-dependent manner. Neutralizing antibodies targeting the EriCoV receptor-binding domain and hedgehog APN effectively blocked EriCoV pseudovirus entry or amplification. Receptor-binding-domain-targeting antibodies were further elucidated by cryogenic electron microscopy analysis. Together, these findings can inform assessment of merbecovirus spillover and pathogenesis.
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Authors: Peng Liu, Qianhui Zhu, Jingyi Liu, Zhixing Ma, Guocui Mou, Yuanling Yu, Chen Liu, 马成宝, Junyu Si, Xiao Yang, Meiling Huang, Yanchu Liu, Yehui Sun, Yu Xiao, Yucheng Sun, Tianci Liu, Lingling Yu, Qianran Wang, Honghao Ma, Qi Lv, Jing Li, Linlin Bao, Yunlong Cao, Xiangxi Wang, Huan Yan
Institutions: Chinese Academy of Sciences, Peking University, Chinese Academy of Medical Sciences & Peking Union Medical College, University of Chinese Academy of Sciences, Center for Life Sciences, Wuhan University, Tsinghua University, Institute of Biophysics, Institute of Laboratory Animal Science