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1.
J Virol ; 96(3): e0192821, 2022 02 09.
Article in English | MEDLINE | ID: covidwho-1691422

ABSTRACT

From 2014 to week 07/2020 the Centre for Health Protection in Hong Kong conducted screening for influenza C virus (ICV). A retrospective analysis of ICV detections to week 26/2019 revealed persistent low-level circulation with outbreaks occurring biennially in the winters of 2015 to 2016 and 2017 to 2018 (R. S. Daniels et al., J Virol 94:e01051-20, 2020, https://doi.org/10.1128/JVI.01051-20). Here, we report on an outbreak occurring in 2019 to 2020, reinforcing the observation of biennial seasonality in Hong Kong. All three outbreaks occurred in similar time frames, were subsequently dwarfed by seasonal epidemics of influenza types A and B, and were caused by similar proportions of C/Kanagawa/1/76 (K)-lineage and C/São Paulo/378/82 S1- and S2-sublineage viruses. Ongoing genetic drift was observed in all genes, with some evidence of amino acid substitution in the hemagglutinin-esterase-fusion (HEF) glycoprotein possibly associated with antigenic drift. A total of 61 ICV genomes covering the three outbreaks were analyzed for reassortment, and 9 different reassortant constellations were identified, 1 K-lineage, 4 S1-sublineage, and 4 S2-sublineage, with 6 of these being identified first in the 2019-1920 outbreak (2 S2-lineage and 4 S1-lineage). The roles that virus interference/enhancement, ICV persistent infection, genome evolution, and reassortment might play in the observed seasonality of ICV in Hong Kong are discussed. IMPORTANCE Influenza C virus (ICV) infection of humans is common, with the great majority of people being infected during childhood, though reinfection can occur throughout life. While infection normally results in "cold-like" symptoms, severe disease cases have been reported in recent years. However, knowledge of ICV is limited due to poor systematic surveillance and an inability to propagate the virus in large amounts in the laboratory. Following recent systematic surveillance in Hong Kong SAR, China, and direct ICV gene sequencing from clinical specimens, a 2-year cycle of disease outbreaks (epidemics) has been identified, with gene mixing playing a significant role in ICV evolution. Studies like those reported here are key to developing an understanding of the impact of influenza C virus infection in humans, notably where comorbidities exist and severe respiratory disease can develop.


Subject(s)
Disease Outbreaks , Influenza, Human/epidemiology , Influenza, Human/virology , Influenzavirus C/classification , Influenzavirus C/genetics , Reassortant Viruses , Hemagglutinins, Viral/chemistry , Hemagglutinins, Viral/genetics , Hong Kong/epidemiology , Humans , Models, Molecular , Mutation , Phylogeny , Public Health Surveillance , Sequence Analysis, DNA , Structure-Activity Relationship , Viral Fusion Proteins/chemistry , Viral Fusion Proteins/genetics
3.
Molecules ; 27(2)2022 Jan 16.
Article in English | MEDLINE | ID: covidwho-1628349

ABSTRACT

Hendra virus (HeV) belongs to the paramyxoviridae family of viruses which is associated with the respiratory distress, neurological illness, and potential fatality of the affected individuals. So far, no competitive approved therapeutic substance is available for HeV. For that reason, the current research work was conducted to propose some novel compounds, by adopting a Computer Aided Drug Discovery approach, which could be used to combat HeV. The G attachment Glycoprotein (Ggp) of HeV was selected to achieve the primary objective of this study, as this protein makes the entry of HeV possible in the host cells. Briefly, a library of 6000 antiviral compounds was screened for potential drug-like properties, followed by the molecular docking of short-listed compounds with the Protein Data Bank (PDB) structure of Ggp. Docked complexes of top two hits, having maximum binding affinities with the active sites of Ggp, were further considered for molecular dynamic simulations of 200 ns to elucidate the results of molecular docking analysis. MD simulations and Molecular Mechanics Energies combined with the Generalized Born and Surface Area (MMGBSA) or Poisson-Boltzmann and Surface Area (MMPBSA) revealed that both docked complexes are stable in nature. Furthermore, the same methodology was used between lead compounds and HeV Ggp in complex with its functional receptor in human, Ephrin-B2. Surprisingly, no major differences were found in the results, which demonstrates that our identified compounds can also perform their action even when the Ggp is attached to the Ephrin-B2 ligand. Therefore, in light of all of these results, we strongly suggest that compounds (S)-5-(benzylcarbamoyl)-1-(2-(4-methyl-2-phenylpiperazin-1-yl)-2-oxoethyl)-6-oxo-3,6-dihydropyridin-1-ium-3-ide and 5-(cyclohexylcarbamoyl)-1-(2-((2-(3-fluorophenyl)-2-methylpropyl)amino)-2-oxoethyl)-6-oxo-3,6-dihydropyridin-1-ium-3-ide could be considered as potential therapeutic agents against HeV; however, further in vitro and in vivo experiments are required to validate this study.


Subject(s)
Antiviral Agents/chemistry , Computational Chemistry/methods , Viral Fusion Proteins/chemistry , Antiviral Agents/metabolism , Ephrin-B2/chemistry , Ephrin-B2/metabolism , Hendra Virus/drug effects , Humans , Hydrogen Bonding , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Receptors, Virus/chemistry , Receptors, Virus/metabolism , Small Molecule Libraries , Viral Fusion Proteins/antagonists & inhibitors , Viral Fusion Proteins/metabolism , Water/chemistry
5.
J Mol Biol ; 433(10): 166946, 2021 05 14.
Article in English | MEDLINE | ID: covidwho-1386061

ABSTRACT

Coronaviruses are a major infectious disease threat, and include the zoonotic-origin human pathogens SARS-CoV-2, SARS-CoV, and MERS-CoV (SARS-2, SARS-1, and MERS). Entry of coronaviruses into host cells is mediated by the spike (S) protein. In our previous ESR studies, the local membrane ordering effect of the fusion peptide (FP) of various viral glycoproteins including the S of SARS-1 and MERS has been consistently observed. We previously determined that the sequence immediately downstream from the S2' cleavage site is the bona fide SARS-1 FP. In this study, we used sequence alignment to identify the SARS-2 FP, and studied its membrane ordering effect. Although there are only three residue differences, SARS-2 FP induces even greater membrane ordering than SARS-1 FP, possibly due to its greater hydrophobicity. This may be a reason that SARS-2 is better able to infect host cells. In addition, the membrane binding enthalpy for SARS-2 is greater. Both the membrane ordering of SARS-2 and SARS-1 FPs are dependent on Ca2+, but that of SARS-2 shows a greater response to the presence of Ca2+. Both FPs bind two Ca2+ ions as does SARS-1 FP, but the two Ca2+ binding sites of SARS-2 exhibit greater cooperativity. This Ca2+ dependence by the SARS-2 FP is very ion-specific. These results show that Ca2+ is an important regulator that interacts with the SARS-2 FP and thus plays a significant role in SARS-2 viral entry. This could lead to therapeutic solutions that either target the FP-calcium interaction or block the Ca2+ channel.


Subject(s)
Calcium/metabolism , Cell Membrane/metabolism , SARS Virus/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Viral Fusion Proteins/metabolism , Amino Acid Sequence , Binding Sites , Calcium/pharmacology , Calorimetry , Cell Membrane/drug effects , Cell Membrane/virology , Hydrogen-Ion Concentration , Hydrophobic and Hydrophilic Interactions , SARS Virus/drug effects , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Thermodynamics , Viral Fusion Proteins/chemistry , Viral Fusion Proteins/genetics , Virus Internalization/drug effects
6.
Molecules ; 26(16)2021 Aug 06.
Article in English | MEDLINE | ID: covidwho-1362397

ABSTRACT

Protein glycosylation that mediates interactions among viral proteins, host receptors, and immune molecules is an important consideration for predicting viral antigenicity. Viral spike proteins, the proteins responsible for host cell invasion, are especially important to be examined. However, there is a lack of consensus within the field of glycoproteomics regarding identification strategy and false discovery rate (FDR) calculation that impedes our examinations. As a case study in the overlap between software, here as a case study, we examine recently published SARS-CoV-2 glycoprotein datasets with four glycoproteomics identification software with their recommended protocols: GlycReSoft, Byonic, pGlyco2, and MSFragger-Glyco. These software use different Target-Decoy Analysis (TDA) forms to estimate FDR and have different database-oriented search methods with varying degrees of quantification capabilities. Instead of an ideal overlap between software, we observed different sets of identifications with the intersection. When clustering by glycopeptide identifications, we see higher degrees of relatedness within software than within glycosites. Taking the consensus between results yields a conservative and non-informative conclusion as we lose identifications in the desire for caution; these non-consensus identifications are often lower abundance and, therefore, more susceptible to nuanced changes. We conclude that present glycoproteomics softwares are not directly comparable, and that methods are needed to assess their overall results and FDR estimation performance. Once such tools are developed, it will be possible to improve FDR methods and quantify complex glycoproteomes with acceptable confidence, rather than potentially misleading broad strokes.


Subject(s)
Algorithms , Glycopeptides/analysis , Glycoproteins/analysis , COVID-19/metabolism , Databases, Protein , Glycopeptides/chemistry , Glycoproteins/chemistry , Glycosylation , Humans , Proteomics/methods , Proteomics/standards , SARS-CoV-2/metabolism , Software , Spike Glycoprotein, Coronavirus/analysis , Spike Glycoprotein, Coronavirus/chemistry , Tandem Mass Spectrometry/methods , Viral Fusion Proteins/analysis , Viral Fusion Proteins/chemistry
7.
Biomed Res Int ; 2021: 9940010, 2021.
Article in English | MEDLINE | ID: covidwho-1259034

ABSTRACT

BACKGROUND: Respiratory syncytial virus (RSV) infection is a public health epidemic, leading to around 3 million hospitalization and about 66,000 deaths each year. It is a life-threatening condition exclusive to children with no effective treatment. METHODS: In this study, we used system-level and vaccinomics approaches to design a polyvalent vaccine for RSV, which could stimulate the immune components of the host to manage this infection. Our framework involves data accession, antigenicity and subcellular localization analysis, T cell epitope prediction, proteasomal and conservancy evaluation, host-pathogen-protein interactions, pathway studies, and in silico binding affinity analysis. RESULTS: We found glycoprotein (G), fusion protein (F), and small hydrophobic protein (SH) of RSV as potential vaccine candidates. Of these proteins (G, F, and SH), we found 9 epitopes for multiple alleles of MHC classes I and II bear significant binding affinity. These potential epitopes were linked to form a polyvalent construct using AAY, GPGPG linkers, and cholera toxin B adjuvant at N-terminal with a 23.9 kDa molecular weight of 224 amino acid residues. The final construct was a stable, immunogenic, and nonallergenic protein containing cleavage sites, TAP transport efficiency, posttranslation shifts, and CTL epitopes. The molecular docking indicated the optimum binding affinity of RSV polyvalent construct with MHC molecules (-12.49 and -10.48 kcal/mol for MHC classes I and II, respectively). This interaction showed that a polyvalent construct could manage and control this disease. CONCLUSION: Our vaccinomics and system-level investigation could be appropriate to trigger the host immune system to prevent RSV infection.


Subject(s)
Computational Biology/methods , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus, Human , Vaccines, Combined/therapeutic use , Alleles , Antigens , Codon , Computer Simulation , Epitopes , Epitopes, T-Lymphocyte , Glycoproteins/chemistry , Histocompatibility Antigens Class I , Histocompatibility Antigens Class II , Hospitalization , Humans , Immune System , Molecular Docking Simulation , Proteasome Endopeptidase Complex , Protein Interaction Mapping , Proteomics , T-Lymphocytes/immunology , Vaccines , Viral Fusion Proteins/chemistry
8.
Proc Natl Acad Sci U S A ; 117(41): 25759-25770, 2020 10 13.
Article in English | MEDLINE | ID: covidwho-807358

ABSTRACT

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 receptor-destroying 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 high-affinity 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, fine-tuned 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.


Subject(s)
Coronavirus/physiology , Hemagglutinins, Viral/genetics , Spike Glycoprotein, Coronavirus/genetics , Viral Fusion Proteins/genetics , Virion/metabolism , Animals , Biological Evolution , Cell Line , Coronavirus/genetics , Coronavirus/metabolism , Coronavirus Infections/virology , Coronavirus OC43, Human/genetics , Coronavirus OC43, Human/metabolism , Coronavirus OC43, Human/physiology , Coronavirus, Bovine/genetics , Coronavirus, Bovine/metabolism , Coronavirus, Bovine/physiology , Hemagglutinins, Viral/chemistry , Hemagglutinins, Viral/metabolism , Humans , Lectins/genetics , Lectins/metabolism , Mice , Mutation , Protein Binding , Protein Domains , Receptors, Virus/metabolism , Selection, Genetic , Sialic Acids/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Viral Fusion Proteins/chemistry , Viral Fusion Proteins/metabolism , Virion/genetics , Virus Attachment , Virus Release
9.
Biophys Chem ; 265: 106438, 2020 10.
Article in English | MEDLINE | ID: covidwho-663111

ABSTRACT

The emerging and re-emerging viral diseases are continuous threats to the wellbeing of human life. Previous outbreaks of Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS had evidenced potential threats of coronaviruses in human health. The recent pandemic due to SARS-CoV-2 is overwhelming and has been going beyond control. Vaccines and antiviral drugs are ungently required to mitigate the pandemic. Therefore, it is important to comprehend the mechanistic details of viral infection process. The fusion between host cell and virus being the first step of infection, understanding the fusion mechanism could provide crucial information to intervene the infection process. Interestingly, all enveloped viruses contain fusion protein on their envelope that acts as fusion machine. For coronaviruses, the spike or S glycoprotein mediates successful infection through receptor binding and cell fusion. The cell fusion process requires merging of virus and host cell membranes, and that is essentially performed by the S2 domain of the S glycoprotein. In this review, we have discussed cell fusion mechanism of SARS-CoV-1 from available atomic resolution structures and membrane binding of fusion peptides. We have further discussed about the cell fusion of SARS-CoV-2 in the context of present pandemic situation.


Subject(s)
Betacoronavirus/physiology , SARS Virus/physiology , Virus Internalization , Humans , Membrane Fusion , Protein Domains , Protein Structure, Secondary , SARS-CoV-2 , Viral Fusion Proteins/chemistry , Viral Fusion Proteins/metabolism
10.
Nat Commun ; 11(1): 2688, 2020 05 27.
Article in English | MEDLINE | ID: covidwho-432476

ABSTRACT

Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses (CoVs) are zoonotic pathogens with high fatality rates and pandemic potential. Vaccine development focuses on the principal target of the neutralizing humoral immune response, the spike (S) glycoprotein. Coronavirus S proteins are extensively glycosylated, encoding around 66-87 N-linked glycosylation sites per trimeric spike. Here, we reveal a specific area of high glycan density on MERS S that results in the formation of oligomannose-type glycan clusters, which were absent on SARS and HKU1 CoVs. We provide a comparison of the global glycan density of coronavirus spikes with other viral proteins including HIV-1 envelope, Lassa virus glycoprotein complex, and influenza hemagglutinin, where glycosylation plays a known role in shielding immunogenic epitopes. Overall, our data reveal how organisation of glycosylation across class I viral fusion proteins influence not only individual glycan compositions but also the immunological pressure across the protein surface.


Subject(s)
Glycoproteins/immunology , Middle East Respiratory Syndrome Coronavirus , Polysaccharides , Spike Glycoprotein, Coronavirus/immunology , Viral Fusion Proteins/immunology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cryoelectron Microscopy , Epitopes/chemistry , Epitopes/immunology , Epitopes/metabolism , Glycoproteins/chemistry , Glycoproteins/ultrastructure , Glycosylation , HEK293 Cells , HIV-1/immunology , HIV-1/metabolism , Humans , Immune Evasion/physiology , Lassa virus/immunology , Lassa virus/metabolism , Middle East Respiratory Syndrome Coronavirus/immunology , Middle East Respiratory Syndrome Coronavirus/metabolism , Orthomyxoviridae/immunology , Orthomyxoviridae/metabolism , Polysaccharides/chemistry , Polysaccharides/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/ultrastructure , Viral Fusion Proteins/chemistry , Viral Fusion Proteins/ultrastructure , Viral Proteins/chemistry , Viral Proteins/immunology , Viral Proteins/ultrastructure
11.
Viruses ; 12(4)2020 04 08.
Article in English | MEDLINE | ID: covidwho-42020

ABSTRACT

Protein-mediated membrane fusion is a highly regulated biological process essential for cellular and organismal functions and infection by enveloped viruses. During viral entry the membrane fusion reaction is catalyzed by specialized protein machinery on the viral surface. These viral fusion proteins undergo a series of dramatic structural changes during membrane fusion where they engage, remodel, and ultimately fuse with the host membrane. The structural and dynamic nature of these conformational changes and their impact on the membranes have long-eluded characterization. Recent advances in structural and biophysical methodologies have enabled researchers to directly observe viral fusion proteins as they carry out their functions during membrane fusion. Here we review the structure and function of type I viral fusion proteins and mechanisms of protein-mediated membrane fusion. We highlight how recent technological advances and new biophysical approaches are providing unprecedented new insight into the membrane fusion reaction.


Subject(s)
Membrane Fusion , Viral Fusion Proteins/chemistry , Viral Fusion Proteins/metabolism , Virus Internalization , Biophysical Phenomena
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