ACE2 from Pipistrellus abramus bats is a receptor for HKU5 coronaviruses
Nicholas Catanzaro, Ziyan Wu, Chengcheng Fan, Victoria A. Jefferson, Anfal Abdelgadir, Alexandra Schäfer, Boyd L. Yount, Pamela J. Björkman, Ralph S. Baric, Michael Letko
Abstract
The merbecovirus subgenus of coronaviruses includes Middle East Respiratory Syndrome Coronavirus (MERS-CoV), a zoonotic pathogen transmitted from dromedary camels to humans that causes severe respiratory disease. Viral discovery efforts uncover hundreds of merbecoviruses in different species across multiple continents, but few are studied under laboratory conditions, leaving basic questions regarding their human threat potential unresolved. Viral entry into host cells is a critical step for transmission between hosts. Here, we develop and apply a scalable approach to assesses novel merbecovirus cell entry across the entire merbecovirus subgenus. Merbecoviruses are sorted into clades based on the receptor-binding domain of the spike glycoprotein. Receptor tropism is clade-specific, with the clade including MERS-CoV using DPP4 and multiple clades using ACE2, including HKU5 bat coronaviruses. Mutational analysis identifies possible structural limitations to HKU5 adaptability and a cryo-EM structure of the HKU5-20s spike trimer reveals only ‘down’ RBDs. This work shows that receptor use in merbecovirus is clade-specific by clustering them into clades based on the receptor-binding domain (RBD) of their spike proteins. While MERS-CoV and its close relatives use the DPP4 receptor, several other clades—including all HKU5 bat coronaviruses—rely on ACE2, the same receptor used by SARS-CoV and SARS-CoV-2.