ETIDIOH - NEW

Abstract Identifying receptors for bat coronaviruses is critical for spillover risk assessment, countermeasure development, and pandemic preparedness . While Middle East respiratory syndrome coronavirus ( MERS-CoV ) uses DPP4 for entry , the receptors of many MERS-related betacoronaviruses remain unknown . The bat merbecovirus HKU5 was previously shown to have an entry restriction in human cells . Using both pseudotyped and full-length virus, we show that HKU5 uses Pipistrellus abramus bat ACE2 but not human ACE2 or DPP4 as a receptor. Cryo-electron microscopy analysis of the virus-receptor complex and structure-guided mutagenesis reveal a spike and ACE2 interaction that is distinct from other ACE2-using coronaviruses. MERS-CoV vaccine sera poorly neutralize HKU5 informing pan-merbecovirus vaccine design. Notably, HKU5 can also engage American mink and stoat ACE2 , revealing mustelids as potential intermediate hosts. These findings highlight the versatility of merbecovirus receptor use...

Abstract Despite accumulating evidence that bat-derived coronaviruses often require intermediate hosts to facilitate transmission to humans1, the potential role of fur animals in zoonotic coronavirus spillovers has largely been overlooked2. Here we report the isolation and characterization of a novel mink respiratory coronavirus (MRCoV) from farmed minks with pneumonia . Notably, MRCoV uses angiotensin-converting enzyme 2 (ACE2) as a receptor and can infect mink, bat, monkey, and human cells . Cryo-electron microscopy analysis revealed that the MRCoV receptor-binding domain (RBD) binds to the same interface on ACE2 receptors as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RBD , despite exhibiting notable structural differences. We identify the key determinants on ACE2 and MRCoV RBD that confer efficient binding. HKU5-33S, a bat coronavirus closely related to MRCoV , utilizes ACE2 of bat Pipistrellus abramus and requires only two amino acid substitutions to adapt to mink...

Highlights •   A distinct HKU5 coronavirus lineage (HKU5-CoV-2) is discovered in bats •  Bat HKU5-CoV-2 uses human ACE2 receptor and ACE2 orthologs from multiple species •   Bat HKU5-CoV-2 RBD engages human ACE2 with a distinct binding mode from other CoVs •  Bat HKU5-CoV-2 was isolated and infect human-ACE2-expressing cells Summary Merbecoviruses comprise four viral species with remarkable genetic diversity: MERS -related coronavirus, Tylonycterisbat coronavirus HKU4, Pipistrellusbat coronavirus HKU5, and Hedgehog coronavirus 1. However, the potential human spillover risk of animal merbecoviruses remains to be investigated. Here, we reported the discovery of HKU5-CoV lineage 2 (HKU5-CoV-2) in bats that efficiently utilize human angiotensin-converting enzyme 2 (ACE2) as a functional receptor and exhibits a broad host tropism . Cryo-EM analysis of HKU5-CoV-2 receptor-binding domain (RBD) and human ACE2 complex revealed an entirely distinct binding mode compared with o...