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.
<abstract> <p>The coronavirus disease 2019 (COVID-2019), a newly emerging disease in China, posed a public health emergency of China. Wuhan is the most serious affected city. Some measures have been taken to control the transmission of COVID-19. From Jan. 23rd, 2020, gradually increasing medical resources (such as health workforce, protective clothing, essential medicines) were sent to Wuhan from other provinces, and the government has established the hospitals to quarantine and treat infected individuals. Under the condition of sufficient medical resources in Wuhan, late-stage of epidemic showed a downward trend. Assessing the effectiveness of medical resources is of great significance for the future response to similar disease. Based on the transmission mechanisms of COVID-19 and epidemic characteristics of Wuhan, by using time-dependent rates for some parameters, we establish a dynamical model to reflect the changes of medical resources on transmission of COVID-19 in Wuhan. Our model is applied to simulate the reported data on cumulative and new confirmed cases in Wuhan from Jan. 23rd to Mar. 6th, 2020. We estimate the basic reproduction number <italic>R</italic><sub>0</sub> = 2.71, which determines whether the disease will eventually die out or not under the absence of effective control measures. Moreover, we calculate the effective daily reproduction ratio <italic>R</italic><sub><italic>e</italic></sub>(<italic>t</italic>), which is used to measure the 'daily reproduction number'. We obtain that <italic>R</italic><sub><italic>e</italic></sub>(<italic>t</italic>) drops less than 1 since Feb. 8th. Our results show that delayed opening the 'Fire God Hill' hospital will greatly increase the magnitude of the outbreak. This shows that the government's timely establishment of hospitals and effective quarantine via quick detection prevent a larger outbreak.</p> </abstract>
Middle East Respiratory Syndrome coronavirus (MERS-CoV) and several bat coronaviruses employ Dipeptidyl peptidase-4 (DPP4) as their functional receptors. However, the receptor for NeoCoV, the closest MERS-CoV relative yet discovered in bats, remains enigmatic. In this study, we unexpectedly found that NeoCoV and its close relative, PDF-2180-CoV, can efficiently use some types of bat Angiotensin-converting enzyme 2 (ACE2) and, less favorably, human ACE2 for entry. The two viruses use their spikes' S1 subunit carboxyl-terminal domains (S1-CTD) for high-affinity and species-specific ACE2 binding. Cryo-electron microscopy analysis revealed a novel coronavirus-ACE2 binding interface and a protein-glycan interaction, distinct from other known ACE2-using viruses. We identified a molecular determinant close to the viral binding interface that restricts human ACE2 from supporting NeoCoV infection, especially around residue Asp338. Conversely, NeoCoV efficiently infects human ACE2 expressing cells after a T510F mutation on the receptor-binding motif (RBM). Notably, the infection could not be cross-neutralized by antibodies targeting SARS-CoV-2 or MERS-CoV. Our study demonstrates the first case of ACE2 usage in MERS-related viruses, shedding light on a potential bio-safety threat of the human emergence of an ACE2 using 'MERS-CoV-2' with both high fatality and transmission rate.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.