scholarly journals Middle East respiratory syndrome coronavirus and bat coronavirus HKU9 both can utilize GRP78 for attachment onto host cells

2018 ◽  
Vol 293 (30) ◽  
pp. 11709-11726 ◽  
Author(s):  
Hin Chu ◽  
Che-Man Chan ◽  
Xi Zhang ◽  
Yixin Wang ◽  
Shuofeng Yuan ◽  
...  
Keyword(s):  
Middle East ◽  
Middle East Respiratory Syndrome ◽  
Host Cells ◽  
Bat Coronavirus

scholarly journals Identification of sialic acid-binding function for the Middle East respiratory syndrome coronavirus spike glycoprotein

2017 ◽  
Vol 114 (40) ◽  
pp. E8508-E8517 ◽  
Author(s):  
Wentao Li ◽  
Ruben J. G. Hulswit ◽  
Ivy Widjaja ◽  
V. Stalin Raj ◽  
Ryan McBride ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Middle East ◽  
Cell Surface ◽  
Human Erythrocytes ◽  
Middle East Respiratory Syndrome ◽  
Host Cells ◽  
Dromedary Camel ◽  
Differential Distribution ◽  
Neuraminidase Treatment ◽  
Intact Virus

Middle East respiratory syndrome coronavirus (MERS-CoV) targets the epithelial cells of the respiratory tract both in humans and in its natural host, the dromedary camel. Virion attachment to host cells is mediated by 20-nm-long homotrimers of spike envelope protein S. The N-terminal subunit of each S protomer, called S1, folds into four distinct domains designated S1A through S1D. Binding of MERS-CoV to the cell surface entry receptor dipeptidyl peptidase 4 (DPP4) occurs via S1B. We now demonstrate that in addition to DPP4, MERS-CoV binds to sialic acid (Sia). Initially demonstrated by hemagglutination assay with human erythrocytes and intact virus, MERS-CoV Sia-binding activity was assigned to S subdomain S1A. When multivalently displayed on nanoparticles, S1 or S1A bound to human erythrocytes and to human mucin in a strictly Sia-dependent fashion. Glycan array analysis revealed a preference for α2,3-linked Sias over α2,6-linked Sias, which correlates with the differential distribution of α2,3-linked Sias and the predominant sites of MERS-CoV replication in the upper and lower respiratory tracts of camels and humans, respectively. Binding is hampered by Sia modifications such as 5-N-glycolylation and (7,)9-O-acetylation. Depletion of cell surface Sia by neuraminidase treatment inhibited MERS-CoV entry of Calu-3 human airway cells, thus providing direct evidence that virus–Sia interactions may aid in virion attachment. The combined observations lead us to propose that high-specificity, low-affinity attachment of MERS-CoV to sialoglycans during the preattachment or early attachment phase may form another determinant governing the host range and tissue tropism of this zoonotic pathogen.

scholarly journals Ca2+ ions promote fusion of Middle East Respiratory Syndrome coronavirus with host cells and increase infectivity

2019 ◽  
Author(s):  
Marco R. Straus ◽  
Tiffany Tang ◽  
Alex L. Lai ◽  
Annkatrin Flegel ◽  
Miya Bidon ◽  
...  
Keyword(s):  
Middle East ◽  
Viral Entry ◽  
Sequence Similarity ◽  
Isothermal Calorimetry ◽  
Mutant Cell ◽  
Proteolytic Cleavage ◽  
Middle East Respiratory Syndrome ◽  
Host Cells ◽  
Cell Surface Expression ◽  
High Sequence Similarity

AbstractMiddle East respiratory syndrome coronavirus (MERS-CoV) is a major emerging zoonotic infectious disease. Since its first outbreak in 2012, the virus has repeatedly transmitted from camels to humans with 2,468 confirmed cases, causing 851 deaths. To date, there are no efficacious drugs and vaccines against MERS-CoV, increasing its potential to cause a public health emergency. A critical step in the life cycle of MERS-CoV is the fusion with the host cell with its spike (S) protein as main determinant of viral entry. Proteolytic cleavage of S exposes its fusion peptide (FP), which initiates membrane fusion. Previous studies on the related severe acute respiratory syndrome coronavirus (SARS-CoV) FP have shown that calcium (Ca2+) plays an important role for fusogenic activity via a Ca2+ binding pocket with conserved glutamic acid (E) and aspartic acid (D) residues. SARS-CoV and MERS-CoV FP share a high sequence homology and here, we investigated whether Ca2+ is required for MERS-CoV fusion by substituting E and D residues in the MERS-CoV FP with neutrally charged alanines. Upon verifying mutant cell surface expression and proteolytic cleavage, we tested the mutants ability to mediate infection of pseudo-particles (PPs) on host cells without and with Ca2+. Our results demonstrate that intracellular Ca2+ enhances MERS-CoV WT PPs infection by approximately two-fold and that E891 is a crucial residue for Ca2+ interaction. Electron spin resonance revealed that this enhancement could be attributed to Ca2+ increasing MERS-CoV FP fusion-relevant membrane ordering. Intriguingly, isothermal calorimetry titration showed that MERS-CoV FP binds one Ca2+, as opposed to SARS-CoV FP which binds two. Our data suggests that there are significant differences in FP-Ca2+ interactions of MERS-CoV and SARS-CoV FP despite their high sequence similarity and that the number of Ca2+ ions interacting with the FP has implications on the fusion dynamics of the virus.

scholarly journals Ca2+ Ions Promote Fusion of Middle East Respiratory Syndrome Coronavirus with Host Cells and Increase Infectivity

2020 ◽  
Vol 94 (13) ◽  
Author(s):  
Marco R. Straus ◽  
Tiffany Tang ◽  
Alex L. Lai ◽  
Annkatrin Flegel ◽  
Miya Bidon ◽  
...  
Keyword(s):  
Middle East ◽  
Molecular Mechanisms ◽  
Sequence Similarity ◽  
Isothermal Calorimetry ◽  
Mutant Cell ◽  
Proteolytic Cleavage ◽  
Middle East Respiratory Syndrome ◽  
Host Cells ◽  
Cell Surface Expression ◽  
S Protein

ABSTRACT Fusion with, and subsequent entry into, the host cell is one of the critical steps in the life cycle of enveloped viruses. For Middle East respiratory syndrome coronavirus (MERS-CoV), the spike (S) protein is the main determinant of viral entry. Proteolytic cleavage of the S protein exposes its fusion peptide (FP), which initiates the process of membrane fusion. Previous studies on the related severe acute respiratory syndrome coronavirus (SARS-CoV) FP have shown that calcium ions (Ca2+) play an important role in fusogenic activity via a Ca2+ binding pocket with conserved glutamic acid (E) and aspartic acid (D) residues. SARS-CoV and MERS-CoV FPs share a high sequence homology, and here, we investigated whether Ca2+ is required for MERS-CoV fusion by screening a mutant array in which E and D residues in the MERS-CoV FP were substituted with neutrally charged alanines (A). Upon verifying mutant cell surface expression and proteolytic cleavage, we tested their ability to mediate pseudoparticle (PP) infection of host cells in modulating Ca2+ environments. Our results demonstrate that intracellular Ca2+ enhances MERS-CoV wild-type (WT) PP infection by approximately 2-fold and that E891 is a crucial residue for Ca2+ interaction. Subsequent electron spin resonance (ESR) experiments revealed that this enhancement could be attributed to Ca2+ increasing MERS-CoV FP fusion-relevant membrane ordering. Intriguingly, isothermal calorimetry showed an approximate 1:1 MERS-CoV FP to Ca2+ ratio, as opposed to an 1:2 SARS-CoV FP to Ca2+ ratio, suggesting significant differences in FP Ca2+ interactions of MERS-CoV and SARS-CoV FP despite their high sequence similarity. IMPORTANCE Middle East respiratory syndrome coronavirus (MERS-CoV) is a major emerging infectious disease with zoonotic potential and has reservoirs in dromedary camels and bats. Since its first outbreak in 2012, the virus has repeatedly transmitted from camels to humans, with 2,468 confirmed cases causing 851 deaths. To date, there are no efficacious drugs and vaccines against MERS-CoV, increasing its potential to cause a public health emergency. In order to develop novel drugs and vaccines, it is important to understand the molecular mechanisms that enable the virus to infect host cells. Our data have found that calcium is an important regulator of viral fusion by interacting with negatively charged residues in the MERS-CoV FP region. This information can guide therapeutic solutions to block this calcium interaction and also repurpose already approved drugs for this use for a fast response to MERS-CoV outbreaks.

scholarly journals Two Mutations Were Critical for Bat-to-Human Transmission of Middle East Respiratory Syndrome Coronavirus

2015 ◽  
Vol 89 (17) ◽  
pp. 9119-9123 ◽  
Author(s):  
Yang Yang ◽  
Chang Liu ◽  
Lanying Du ◽  
Shibo Jiang ◽  
Zhengli Shi ◽  
...  
Keyword(s):  
Middle East ◽  
Viral Entry ◽  
Human Cells ◽  
Middle East Respiratory Syndrome ◽  
Intermediate Hosts ◽  
Virus Surface ◽  
Bat Coronavirus ◽  
Do So

To understand how Middle East respiratory syndrome coronavirus (MERS-CoV) transmitted from bats to humans, we compared the virus surface spikes of MERS-CoV and a related bat coronavirus, HKU4. Although HKU4 spike cannot mediate viral entry into human cells, two mutations enabled it to do so by allowing it to be activated by human proteases. These mutations are present in MERS-CoV spike, explaining why MERS-CoV infects human cells. These mutations therefore played critical roles in the bat-to-human transmission of MERS-CoV, either directly or through intermediate hosts.

scholarly journals Discovery of Novel Bat Coronaviruses in South China That Use the Same Receptor as Middle East Respiratory Syndrome Coronavirus

2018 ◽  
Vol 92 (13) ◽  
Author(s):  
Chu-Ming Luo ◽  
Ning Wang ◽  
Xing-Lou Yang ◽  
Hai-Zhou Liu ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Middle East ◽  
South China ◽  
Middle East Respiratory Syndrome ◽  
Epidemiological Surveillance ◽  
Content Type ◽  
Dipeptidyl Peptidase 4 ◽  
Protein Protein Interaction ◽  
Evolutionary Origins ◽  
Bat Coronavirus ◽  
Spike Proteins

ABSTRACTMiddle East respiratory syndrome coronavirus (MERS-CoV) has represented a human health threat since 2012. Although several MERS-related CoVs that belong to the same species as MERS-CoV have been identified from bats, they do not use the MERS-CoV receptor, dipeptidyl peptidase 4 (DPP4). Here, we screened 1,059 bat samples from at least 30 bat species collected in different regions in south China and identified 89 strains of lineage C betacoronaviruses, includingTylonycteris pachypus coronavirus HKU4,Pipistrellus pipistrelluscoronavirus HKU5, and MERS-related CoVs. We sequenced the full-length genomes of two positive samples collected from the great evening bat,Ia io, from Guangdong Province. The two genomes were highly similar and exhibited genomic structures identical to those of other lineage C betacoronaviruses. While they exhibited genome-wide nucleotide identities of only 75.3 to 81.2% with other MERS-related CoVs, their gene-coding regions were highly similar to their counterparts, except in the case of the spike proteins. Further protein-protein interaction assays demonstrated that the spike proteins of these MERS-related CoVs bind to the receptor DPP4. Recombination analysis suggested that the newly discovered MERS-related CoVs have acquired their spike genes from a DPP4-recognizing bat coronavirus HKU4. Our study provides further evidence that bats represent the evolutionary origins of MERS-CoV.IMPORTANCEPrevious studies suggested that MERS-CoV originated in bats. However, its evolutionary path from bats to humans remains unclear. In this study, we discovered 89 novel lineage C betacoronaviruses in eight bat species. We provide evidence of a MERS-related CoV derived from the great evening bat that uses the same host receptor as human MERS-CoV. This virus also provides evidence for a natural recombination event between the bat MERS-related CoV and another bat coronavirus, HKU4. Our study expands the host ranges of MERS-related CoV and represents an important step toward establishing bats as the natural reservoir of MERS-CoV. These findings may lead to improved epidemiological surveillance of MERS-CoV and the prevention and control of the spread of MERS-CoV to humans.

Massive Infektion und alveolare Schädigung der humanen Lunge durch das Middle East Respiratory Syndrome Coronavirus (MERS-CoV)

Pneumologie ◽  
2015 ◽  
Vol 69 (04) ◽  
Author(s):  
A Becher ◽  
J von Recum ◽  
K Schierhorn ◽  
T Wolff ◽  
M Tönnies ◽  
...  
Keyword(s):  
Middle East ◽  
Middle East Respiratory Syndrome

Aerogen übertragene Infektionskrankheiten bei Kindern auf Reisen

2018 ◽  
Vol 18 (06) ◽  
pp. 422-426
Author(s):  
C. Rau ◽  
J. Lindert ◽  
S. Kotsias-Konopelska ◽  
R. Kobbe
Keyword(s):  
Middle East ◽  
Middle East Respiratory Syndrome ◽  
Bakterielle Infektionen ◽  
Saisonale Influenza

ZusammenfassungErkrankungen der Atemwege gehören zu den häufigsten Gesundheitsproblemen von Kindern und treten regelhaft auch während und nach Reisen auf. Virale Atemwegsinfektionen können die Reisefähigkeit von Kindern – und damit auch ihren Angehörigen – ungünstig beeinflussen, beispielsweise durch Fieber, bronchiale Obstruktion und Schwierigkeiten beim Druckausgleich während des Fliegens durch Schwellungen und Sekretionen der Schleimhäute und der eustachi‘schen Röhre. Zu den reisemedizinisch relevanten aerogen übertragenen Krankheiten zählen neben banalen, viralen Erkältungen auch potenziell schwer verlaufende Viruserkrankungen, allen voran die saisonale Influenza und die Masern, sowie bakterielle Infektionen durch Meningokokken und die Tuberkulose. Gegen einige dieser Erkrankungen stehen effektive Impfstoffe zur Verfügung. Auch seltene, schwer verlaufende Atemwegsinfektionen, die unter bestimmten epidemiologischen Umständen außerhalb Europas erworben werden können, sollen im Folgenden exemplarisch an den Erkrankungen Middle East respiratory syndrome (MERS) und der Histoplasmose dargestellt werden.

Lead Molecule Prediction and Characterization for Designing MERS-CoV 3C-like Protease Inhibitors: An In silico Approach

2018 ◽  
Vol 15 (1) ◽  
pp. 82-88 ◽  
Author(s):  
Md. Mostafijur Rahman ◽  
Md. Bayejid Hosen ◽  
M. Zakir Hossain Howlader ◽  
Yearul Kabir
Keyword(s):  
Binding Energy ◽  
Middle East ◽  
Virtual Screening ◽  
In Silico ◽  
Screening Method ◽  
Middle East Respiratory Syndrome ◽  
Cytochrome P450 Enzymes ◽  
Drug Molecules ◽  
Essential Enzyme ◽  
Reduced Toxicity

Background: 3C-like protease also called the main protease is an essential enzyme for the completion of the life cycle of Middle East Respiratory Syndrome Coronavirus. In our study we predicted compounds which are capable of inhibiting 3C-like protease, and thus inhibit the lifecycle of Middle East Respiratory Syndrome Coronavirus using in silico methods. </P><P> Methods: Lead like compounds and drug molecules which are capable of inhibiting 3C-like protease was identified by structure-based virtual screening and ligand-based virtual screening method. Further, the compounds were validated through absorption, distribution, metabolism and excretion filtering. Results: Based on binding energy, ADME properties, and toxicology analysis, we finally selected 3 compounds from structure-based virtual screening (ZINC ID: 75121653, 41131653, and 67266079) having binding energy -7.12, -7.1 and -7.08 Kcal/mol, respectively and 5 compounds from ligandbased virtual screening (ZINC ID: 05576502, 47654332, 04829153, 86434515 and 25626324) having binding energy -49.8, -54.9, -65.6, -61.1 and -66.7 Kcal/mol respectively. All these compounds have good ADME profile and reduced toxicity. Among eight compounds, one is soluble in water and remaining 7 compounds are highly soluble in water. All compounds have bioavailability 0.55 on the scale of 0 to 1. Among the 5 compounds from structure-based virtual screening, 2 compounds showed leadlikeness. All the compounds showed no inhibition of cytochrome P450 enzymes, no blood-brain barrier permeability and no toxic structure in medicinal chemistry profile. All the compounds are not a substrate of P-glycoprotein. Our predicted compounds may be capable of inhibiting 3C-like protease but need some further validation in wet lab.

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