A key unsolved question in the current coronavirus disease 2019 (COVID-19) pandemic is the duration of acquired immunity. Insights from infections with the four seasonal human coronaviruses might ...reveal common characteristics applicable to all human coronaviruses. We monitored healthy individuals for more than 35 years and determined that reinfection with the same seasonal coronavirus occurred frequently at 12 months after infection.
Recent outbreaks of severe acute respiratory syndrome and Middle East respiratory syndrome, along with the threat of a future coronavirus-mediated pandemic, underscore the importance of finding ways ...to combat these viruses. The trimeric spike transmembrane glycoprotein S mediates entry into host cells and is the major target of neutralizing antibodies. To understand the humoral immune response elicited upon natural infections with coronaviruses, we structurally characterized the SARS-CoV and MERS-CoV S glycoproteins in complex with neutralizing antibodies isolated from human survivors. Although the two antibodies studied blocked attachment to the host cell receptor, only the anti-SARS-CoV S antibody triggered fusogenic conformational changes via receptor functional mimicry. These results provide a structural framework for understanding coronavirus neutralization by human antibodies and shed light on activation of coronavirus membrane fusion, which takes place through a receptor-driven ratcheting mechanism.
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•MERS-CoV/SARS-CoV S composite glycan shields analyzed by cryo-EM and mass spectrometry•Structures of MERS-CoV/SARS-CoV S with neutralizing antibodies from survivors•LCA60 inhibits receptor binding by interacting with MERS-CoV S protein/glycans•S230 blocks receptor binding and triggers fusogenic rearrangements via functional mimicry
Structural analysis of the SARS-CoV S and MERS-CoV S glycoproteins in complex with neutralizing antibodies from human survivors sheds light into the mechanisms of membrane fusion and neutralization
From the beginning of 2002 and 2012, severe respiratory syndrome coronavirus (SARS‐CoV) and Middle East respiratory syndrome coronavirus (MERS‐CoV) crossed the species barriers to infect humans, ...causing thousands of infections and hundreds of deaths, respectively. Currently, a novel coronavirus (SARS‐CoV‐2), which has become the cause of the outbreak of Coronavirus Disease 2019 (COVID‐19), was discovered. Until 18 February 2020, there were 72 533 confirmed COVID‐19 cases (including 10 644 severe cases) and 1872 deaths in China. SARS‐CoV‐2 is spreading among the public and causing substantial burden due to its human‐to‐human transmission. However, the intermediate host of SARS‐CoV‐2 is still unclear. Finding the possible intermediate host of SARS‐CoV‐2 is imperative to prevent further spread of the epidemic. In this study, we used systematic comparison and analysis to predict the interaction between the receptor‐binding domain (RBD) of coronavirus spike protein and the host receptor, angiotensin‐converting enzyme 2 (ACE2). The interaction between the key amino acids of S protein RBD and ACE2 indicated that, other than pangolins and snakes, as previously suggested, turtles (Chrysemys picta bellii, Chelonia mydas, and Pelodiscus sinensis) may act as the potential intermediate hosts transmitting SARS‐CoV‐2 to humans.
Highlights
The critical residues of S protein RBD binding with ACE2 indicated the potential intermediate hosts transmitting SARS‐CoV‐2 to humans.
A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) recently emerged and is rapidly spreading in humans, causing COVID-19
. A key to tackling this pandemic is to understand ...the receptor recognition mechanism of the virus, which regulates its infectivity, pathogenesis and host range. SARS-CoV-2 and SARS-CoV recognize the same receptor-angiotensin-converting enzyme 2 (ACE2)-in humans
. Here we determined the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 (engineered to facilitate crystallization) in complex with ACE2. In comparison with the SARS-CoV RBD, an ACE2-binding ridge in SARS-CoV-2 RBD has a more compact conformation; moreover, several residue changes in the SARS-CoV-2 RBD stabilize two virus-binding hotspots at the RBD-ACE2 interface. These structural features of SARS-CoV-2 RBD increase its ACE2-binding affinity. Additionally, we show that RaTG13, a bat coronavirus that is closely related to SARS-CoV-2, also uses human ACE2 as its receptor. The differences among SARS-CoV-2, SARS-CoV and RaTG13 in ACE2 recognition shed light on the potential animal-to-human transmission of SARS-CoV-2. This study provides guidance for intervention strategies that target receptor recognition by SARS-CoV-2.
This paper continues a recent study of the spike protein sequence of the COVID-19 virus (SARS-CoV-2). It is also in part an introductory review to relevant computational techniques for tackling viral ...threats, using COVID-19 as an example. Q-UEL tools for facilitating access to knowledge and bioinformatics tools were again used for efficiency, but the focus in this paper is even more on the virus. Subsequence KRSFIEDLLFNKV of the S2′ spike glycoprotein proteolytic cleavage site continues to appear important. Here it is shown to be recognizable in the common cold coronaviruses, avian coronaviruses and possibly as traces in the nidoviruses of reptiles and fish. Its function or functions thus seem important to the coronaviruses. It might represent SARS-CoV-2 Achilles’ heel, less likely to acquire resistance by mutation, as has happened in some early SARS vaccine studies discussed in the previous paper. Preliminary conformational analysis of the receptor (ACE2) binding site of the spike protein is carried out suggesting that while it is somewhat conserved, it appears to be more variable than KRSFIEDLLFNKV. However compounds like emodin that inhibit SARS entry, apparently by binding ACE2, might also have functions at several different human protein binding sites. The enzyme 11β-hydroxysteroid dehydrogenase type 1 is again argued to be a convenient model pharmacophore perhaps representing an ensemble of targets, and it is noted that it occurs both in lung and alimentary tract. Perhaps it benefits the virus to block an inflammatory response by inhibiting the dehydrogenase, but a fairly complex web involves several possible targets.
•This paper “drills down” into the studies of the author's previous COVID-19 paper.•Designing vaccine and drugs must seek to avoid escape mutations.•Subsequence KRSFIEDLLFNKV seems recognizable across many coronaviruses.•The ACE2 binding domain is a target, but shows variation.•A steroid dehydrogenase is argued to remain an interesting model pharmacophore.
Human coronaviruses OC43 and HKU1 are respiratory pathogens of zoonotic origin that have gained worldwide distribution. OC43 apparently emerged from a bovine coronavirus (BCoV) spillover. All three ...viruses attach to 9-O-acetylated sialoglycans via spike protein S with hemagglutinin-esterase (HE) acting as a receptordestroying enzyme. In BCoV, an HE lectin domain promotes esterase activity toward clustered substrates. OC43 and HKU1, however, lost HE lectin function as an adaptation to humans. Replaying OC43 evolution, we knocked out BCoV HE lectin function and performed forced evolution-population dynamics analysis. Loss of HE receptor binding selected for second-site mutations in S, decreasing S binding affinity by orders of magnitude. Irreversible HE mutations led to cooperativity in virus swarms with low-affinity S minority variants sustaining propagation of highaffinity majority phenotypes. Salvageable HE mutations induced successive second-site substitutions in both S and HE. Apparently, S and HE are functionally interdependent and coevolve to optimize the balance between attachment and release. This mechanism of glycan-based receptor usage, entailing a concerted, finetuned activity of two envelope protein species, is unique among CoVs, but reminiscent of that of influenza A viruses. Apparently, general principles fundamental to virion–sialoglycan interactions prompted convergent evolution of two important groups of human and animal pathogens.
The recently reported Middle East respiratory syndrome coronavirus (MERS-CoV) is phylogenetically closely related to the bat coronaviruses (BatCoVs) HKU4 and HKU5. However, the evolutionary pathway ...of MERS-CoV is still unclear. A receptor binding domain (RBD) in the MERS-CoV envelope-embedded spike protein specifically engages human CD26 (hCD26) to initiate viral entry. The high sequence identity in the viral spike protein prompted us to investigate if HKU4 and HKU5 can recognize hCD26 for cell entry. We found that HKU4-RBD, but not HKU5-RBD, binds to hCD26, and pseudotyped viruses embedding HKU4 spike can infect cells via hCD26 recognition. The structure of the HKU4-RBD/hCD26 complex revealed a hCD26-binding mode similar overall to that observed for MERS-RBD. HKU4-RBD, however, is less adapted to hCD26 than MERS-RBD, explaining its lower affinity for receptor binding. Our findings support a bat origin for MERS-CoV and indicate the need for surveillance of HKU4-related viruses in bats.
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•The bat coronavirus HKU4 is phylogenetically closely related to MERS-CoV•The BatCoV HKU4, but not HUK5, spike protein binds to the MERS-CoV human receptor hCD26•Virus particles pseudotyped with BatCoV HKU4 spike infect cells by engaging hCD26•HKU4-RBD/hCD26 structure delineates the recognition basis and interaction details
Bat origin has been suggested for the recently identified MERS coronavirus (CoV). Wang et al. provide structural and functional evidence that bat coronavirus HKU4 can utilize the MERS-CoV human receptor CD26 for cell entry. These studies support the possible adaptation of HKU4 coronavirus to infect humans and the need for continued surveillance.
The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses ...depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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•SARS-CoV-2 uses the SARS-CoV receptor ACE2 for host cell entry•The spike protein of SARS-CoV-2 is primed by TMPRSS2•Antibodies against SARS-CoV spike may offer some protection against SARS-CoV-2
The emerging SARS-coronavirus 2 (SARS-CoV-2) threatens public health. Hoffmann and coworkers show that SARS-CoV-2 infection depends on the host cell factors ACE2 and TMPRSS2 and can be blocked by a clinically proven protease inhibitor. These findings might help to establish options for prevention and treatment.
SARS-CoV-2, a new coronavirus strain responsible for COVID-19, has emerged in Wuhan City, China, and continuing its global pandemic nature. The availability of the complete gene sequences of the ...virus helps to know about the origin and molecular characteristics of this virus. In the present study, we performed bioinformatic analysis of the available gene sequence data of SARS-CoV-2 for the understanding of evolution and molecular characteristics and immunogenic resemblance of the circulating viruses. Phylogenetic analysis was performed for four types of representative viral proteins (spike, membrane, envelope and nucleoprotein) of SARS-CoV-2, HCoV-229E, HCoV-OC43, SARS-CoV, HCoV-NL63, HKU1, MERS-CoV, HKU4, HKU5 and BufCoV-HKU26. The findings demonstrated that SARS-CoV-2 exhibited convergent evolutionary relation with previously reported SARS-CoV. It was also depicted that SARS-CoV-2 proteins were highly similar and identical to SARS-CoV proteins, though proteins from other coronaviruses showed a lower level of resemblance. The cross-checked conservancy analysis of SARS-CoV-2 antigenic epitopes showed significant conservancy with antigenic epitopes derived from SARS-CoV. Descriptive epidemiological analysis on several epidemiological indices was performed on available epidemiological outbreak information from several open databases on COVID-19 (SARS-CoV-2). Satellite-derived imaging data have been employed to understand the role of temperature in the environmental persistence of the virus. Findings of the descriptive analysis were used to describe the global impact of newly emerged SARS-CoV-2, and the risk of an epidemic in Bangladesh.
•Phylogenetic tree clearly demonstrating the ancestral origin and distant evolutionary relationships of the newly epidemic novel coronavirus SARS-CoV-2.•SARS-CoV-2 proteins showed highest level of similarity and identical patterns with SARS-CoV.•SARS-CoV-2 antigenic epitopes were significantly conserved with antigenic epitopes derived from SARS-CoV.•COVID-19 poses a great burden across the world in terms of geographical coverage, occurrence of cases and death toll.
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