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Published on: November 5, 2021
ACE2 utilization of HKU25 clade MERS-related coronaviruses with broad geographic distribution
Chen Liu1, Young-Jun Park2,3, Cheng-Bao Ma1
1State Key Laboratory of Virology and Biosafety, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University; Wuhan, Hubei, 430072, China.
Abstract:
Dipeptidyl peptidase-4 (DPP4) is a well-established receptor for several MERS-related coronaviruses (MERSr-CoVs) isolated from humans, camels, pangolins, and bats (1-6). However, the receptor usage of many genetically diverse bat MERSr-CoVs with broad geographical distributions remains poorly understood. Recent studies have identified angiotensin-converting enzyme 2 (ACE2) as an entry receptor for multiple merbecovirus clades. Here, using viral antigen and pseudovirus-based functional assays, we demonstrate that several bat merbecoviruses from the HKU25 clade previously thought to utilize DPP4 (7), employ ACE2 as their functional receptor. Cryo-electron microscopy analysis revealed that HsItaly2011 and VsCoV-a7 recognize ACE2 with a binding mode sharing similarity with that of HKU5 but involving remodeled interfaces and distinct ortholog selectivity, suggesting a common evolutionary origin of ACE2 utilization for these two clades of viruses. EjCoV-3, a strain closely related to the DPP4-using MERSr-CoV BtCoV-422, exhibited relatively broad ACE2 ortholog tropism and could utilize human ACE2 albeit suboptimally. Despite differences in entry mechanisms and spike proteolytic activation compared to MERS-CoV, these viruses remain sensitive to several broadly neutralizing antibodies and entry inhibitors. These findings redefine our understanding of the evolution of receptor usage among MERSr-CoVs and highlight the versatility of ACE2 as a functional receptor for diverse coronaviruses.
Insights
Many bat coronaviruses previously thought to use DPP4 actually use ACE2 for cell entry. This finding expands our understanding of coronavirus receptor usage and evolution.
Area of Science:
- Virology
- Molecular Biology
- Evolutionary Biology
Background:
- Dipeptidyl peptidase-4 (DPP4) is a known receptor for MERS-related coronaviruses (MERSr-CoVs) from various hosts.
- Receptor usage for many diverse bat MERSr-CoVs remains unclear.
- Angiotensin-converting enzyme 2 (ACE2) has recently emerged as an entry receptor for merbecoviruses.
Purpose of the Study:
- To investigate the functional receptor usage of bat MERSr-CoVs, particularly those from the HKU25 clade.
- To understand the evolutionary origins of ACE2 utilization among different merbecovirus clades.
- To assess the susceptibility of these viruses to neutralizing antibodies and entry inhibitors.
Main Methods:
- Viral antigen and pseudovirus-based functional assays were employed.
- Cryo-electron microscopy was used to analyze virus-receptor interactions.
- ACE2 ortholog tropism and human ACE2 utilization were assessed.
Main Results:
- Several bat merbecoviruses from the HKU25 clade, previously believed to use DPP4, were found to utilize ACE2.
- Cryo-EM revealed ACE2 binding modes similar to HKU5 but with distinct interfaces and ortholog selectivity.
- EjCoV-3 showed broad ACE2 ortholog tropism and suboptimal human ACE2 utilization.
- Despite entry mechanism differences, viruses remained sensitive to neutralizing antibodies and entry inhibitors.
Conclusions:
- Bat merbecoviruses, including those in the HKU25 clade, can use ACE2 as a functional receptor.
- ACE2 utilization has evolved independently or convergently among different merbecovirus clades.
- These findings broaden the understanding of MERSr-CoV receptor tropism and evolution.
- ACE2 is a versatile receptor for diverse coronaviruses, with implications for zoonotic potential.
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