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1.
Viruses ; 14(4)2022 03 29.
Article in English | MEDLINE | ID: covidwho-1810312

ABSTRACT

The complete nucleotide sequence of the S1 glycoprotein gene of the Japanese infectious bronchitis virus (IBV) strains was determined and genetically analyzed. A total of 61 Japanese IBV strains were classified into seven genotypes, namely GI-1, 3, 7, 13, 18, 19, and GVI-1 using the classification scheme that was proposed by Valastro et al, with three exceptions. These genotypes practically corresponded to those defined in Japan, namely Mass, Gray, JP-II, 4/91, JP-I, JP-III, and JP-IV, which have been identified through their partial nucleotide sequences containing hypervariable regions 1 and 2. In addition, three exceptive strains were considered to be derived from recombination within the S1 gene of IBV strains G1-13 and GI-19. By analyzing the amino acid polymorphism of the S1 glycoprotein among Japanese genotypes, a diversity was observed based on the genotype-specific amino acid residue, the proteolytic cleavage motif at the S1/S2 cleavage site, and the position of the potential N-glycosylation sites.


Subject(s)
Coronavirus Infections , Infectious bronchitis virus , Poultry Diseases , Amino Acids/genetics , Animals , Chickens , Coronavirus Infections/veterinary , Glycoproteins/genetics , Infectious bronchitis virus/genetics , Japan , Phylogeny
2.
Development ; 149(1)2022 01 01.
Article in English | MEDLINE | ID: covidwho-1799075

ABSTRACT

Imprinting control region (ICR1) controls the expression of the Igf2 and H19 genes in a parent-of-origin specific manner. Appropriate expression of the Igf2-H19 locus is fundamental for normal fetal development, yet the importance of ICR1 in the placental production of hormones that promote maternal nutrient allocation to the fetus is unknown. To address this, we used a novel mouse model to selectively delete ICR1 in the endocrine junctional zone (Jz) of the mouse placenta (Jz-ΔICR1). The Jz-ΔICR1 mice exhibit increased Igf2 and decreased H19 expression specifically in the Jz. This was accompanied by an expansion of Jz endocrine cell types due to enhanced rates of proliferation and increased expression of pregnancy-specific glycoprotein 23 in the placenta of both fetal sexes. However, changes in the endocrine phenotype of the placenta were related to sexually-dimorphic alterations to the abundance of Igf2 receptors and downstream signalling pathways (Pi3k-Akt and Mapk). There was no effect of Jz-ΔICR1 on the expression of targets of the H19-embedded miR-675 or on fetal weight. Our results demonstrate that ICR1 controls placental endocrine capacity via sex-dependent changes in signalling.


Subject(s)
Endocrine Glands/metabolism , Insulin-Like Growth Factor II/genetics , Locus Control Region , Placenta/metabolism , RNA, Long Noncoding/genetics , Signal Transduction , Animals , Female , Genetic Loci , Genomic Imprinting , Glycoproteins/genetics , Glycoproteins/metabolism , Insulin-Like Growth Factor II/metabolism , Male , Mice , Mice, Inbred C57BL , Phosphatidylinositol 3-Kinases/metabolism , Pregnancy , Pregnancy Proteins/genetics , Pregnancy Proteins/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA, Long Noncoding/metabolism
3.
Proc Natl Acad Sci U S A ; 119(16): e2119680119, 2022 04 19.
Article in English | MEDLINE | ID: covidwho-1768985

ABSTRACT

Muco-obstructive lung diseases are typically associated with high risks of COVID-19 severity; however, allergic asthma showed reduced susceptibility. To investigate viral spread, primary human airway epithelial (HAE) cell cultures were infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and host­virus interactions were examined via electron microscopy, immunohistochemistry, RNA in situ hybridization, and gene expression analyses. In HAE cell cultures, angiotensin-converting enzyme 2 (ACE2) expression governed cell tropism and viral load and was up-regulated by infection. Electron microscopy identified intense viral egress from infected ciliated cells and severe cytopathogenesis, culminating in the shedding of ciliated cells packed with virions, providing a large viral reservoir for spread and transmission. Intracellular stores of MUC5AC, a major airway mucin involved in asthma, were rapidly depleted, likely to trap viruses. To mimic asthmatic airways, HAE cells were treated with interleukin-13 (IL-13), which reduced viral titers, viral messenger RNA, and cell shedding, and significantly diminished the number of infected cells. Although mucus hyperproduction played a shielding role, IL-13­treated cells maintained a degree of protection despite the removal of mucus. Using Gene Expression Omnibus databases, bulk RNA-sequencing analyses revealed that IL-13 up-regulated genes controlling glycoprotein synthesis, ion transport, and antiviral processes (albeit not the typical interferon-induced genes) and down-regulated genes involved in cilial function and ribosomal processing. More precisely, we showed that IL-13 reduced ACE2 expression, intracellular viral load, and cell-to-cell transmission while increasing the cilial keratan sulfate coating. In conclusion, intense viral and cell shedding caused by SARS-CoV-2 infection was attenuated by IL-13, which affected viral entry, replication, and spread.


Subject(s)
COVID-19 , Interleukin-13 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/virology , Glycoproteins/genetics , Glycoproteins/metabolism , Humans , Interleukin-13/metabolism , Respiratory System/virology
4.
Int J Biol Macromol ; 208: 105-125, 2022 May 31.
Article in English | MEDLINE | ID: covidwho-1751045

ABSTRACT

Late in 2019, SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) emerged, causing an unknown type of pneumonia today called coronaviruses disease 2019 (COVID-19). COVID-19 is still an ongoing global outbreak that has claimed and threatened many lives worldwide. Along with the fastest vaccine developed in history to fight SARS-CoV-2 came a critical problem, SARS-CoV-2. These new variants are a result of the accumulation of mutations in the sequence and structure of spike (S) glycoprotein, which is by far the most critical protein for SARS-CoV-2 to recognize cells and escape the immune system, in addition to playing a role in SARS-CoV-2 infection, pathogenicity, transmission, and evolution. In this review, we discuss mutation of S protein and how these mutations have led to new variants that are usually more transmissible and can thus mitigate the immunity produced by vaccination. Here, analysis of S protein sequences and structures from variants point out the mutations among them, how they emerge, and the behavior of S protein from each variant. This review brings details in an understandable way about how the variants of SARS-CoV-2 are a result of mutations in S protein, making them more transmissible and even more aggressive than their relatives.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/epidemiology , Glycoproteins/genetics , Humans , Mutation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/metabolism
5.
Geroscience ; 44(2): 619-637, 2022 04.
Article in English | MEDLINE | ID: covidwho-1729366

ABSTRACT

The Omicron variant has been detected in nearly 150 countries. We analyzed the mutational landscape of Omicron throughout the genome, focusing the S-glycoprotein. We also evaluated mutations in the antibody-binding regions and observed some important mutations overlapping those of previous variants including N501Y, D614G, H655Y, N679K, and P681H. Various new receptor-binding domain mutations were detected, including Q493K, G496S, Q498R, S477N, G466S, N440K, and Y505H. New mutations were found in the NTD (Δ143-145, A67V, T95I, L212I, and Δ211) including one new mutation in fusion peptide (D796Y). There are several mutations in the antibody-binding region including K417N, E484A, Q493K, Q498R, N501Y, and Y505H and several near the antibody-binding region (S477N, T478K, G496S, G446S, and N440K). The impact of mutations in regions important for the affinity between spike proteins and neutralizing antibodies was evaluated. Furthermore, we examined the effect of significant antibody-binding mutations (K417N, T478K, E484A, and N501Y) on antibody affinity, stability to ACE2 interaction, and possibility of amino acid substitution. All the four mutations destabilize the antibody-binding affinity. This study reveals future directions for developing neutralizing antibodies against the Omicron variant.


Subject(s)
COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Antibodies, Neutralizing/genetics , COVID-19/genetics , Glycoproteins/genetics , Humans , Mutation/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
7.
Biosci Rep ; 42(2)2022 02 25.
Article in English | MEDLINE | ID: covidwho-1655685

ABSTRACT

Lassa virus (LASV), an arenavirus endemic to West Africa, causes Lassa fever-a lethal hemorrhagic fever. Entry of LASV into the host cell is mediated by the glycoprotein complex (GPC), which is the only protein located on the viral surface and comprises three subunits: glycoprotein 1 (GP1), glycoprotein 2 (GP2), and a stable signal peptide (SSP). The LASV GPC is a class one viral fusion protein, akin to those found in viruses such as human immunodeficiency virus (HIV), influenza, Ebola virus (EBOV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These viruses are enveloped and utilize membrane fusion to deliver their genetic material to the host cell. Like other class one fusion proteins, LASV-mediated membrane fusion occurs through an orchestrated sequence of conformational changes in its GPC. The receptor-binding subunit, GP1, first engages with a host cell receptor then undergoes a unique receptor switch upon delivery to the late endosome. The acidic pH and change in receptor result in the dissociation of GP1, exposing the fusion subunit, GP2, such that fusion can occur. These events ultimately lead to the formation of a fusion pore so that the LASV genetic material is released into the host cell. Interestingly, the mature GPC retains its SSP as a third subunit-a feature that is unique to arenaviruses. Additionally, the fusion domain contains two separate fusion peptides, instead of a standard singular fusion peptide. Here, we give a comprehensive review of the LASV GPC components and their unusual features.


Subject(s)
Glycoproteins , Lassa virus , Viral Envelope Proteins , Glycoproteins/genetics , Humans , Lassa virus/genetics , Viral Envelope Proteins/genetics , Virus Internalization
8.
J Med Chem ; 64(19): 14332-14343, 2021 10 14.
Article in English | MEDLINE | ID: covidwho-1621195

ABSTRACT

In addition to a variety of viral-glycoprotein receptors (e.g., heparan sulfate, Niemann-Pick C1, etc.), dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), from the C-type lectin receptor family, plays one of the most important pathogenic functions for a wide range of viruses (e.g., Ebola, human cytomegalovirus (HCMV), HIV-1, severe acute respiratory syndrome coronavirus 2, etc.) that invade host cells before replication; thus, its inhibition represents a relevant extracellular antiviral therapy. We report two novel p-tBu-calixarene glycoclusters 1 and 2, bearing tetrahydroxamic acid groups, which exhibit micromolar inhibition of soluble DC-SIGN binding and provide nanomolar IC50 inhibition of both DC-SIGN-dependent Jurkat cis-cell infection by viral particle pseudotyped with Ebola virus glycoprotein and the HCMV-gB-recombinant glycoprotein interaction with monocyte-derived dendritic cells expressing DC-SIGN. A unique cooperative involvement of sugar, linker, and calixarene core is likely behind the strong avidity of DC-SIGN for these low-valent systems. We claim herein new promising candidates for the rational development of a large spectrum of antiviral therapeutics.


Subject(s)
Calixarenes/chemistry , Cell Adhesion Molecules/antagonists & inhibitors , Glycoconjugates/metabolism , Glycoproteins/antagonists & inhibitors , Hydroxamic Acids/chemistry , Lectins, C-Type/antagonists & inhibitors , Phenols/chemistry , Receptors, Cell Surface/antagonists & inhibitors , Viral Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Cell Adhesion Molecules/metabolism , Cell Line , Cytomegalovirus/metabolism , Dendritic Cells/cytology , Dendritic Cells/metabolism , Ebolavirus/physiology , Glycoconjugates/chemistry , Glycoconjugates/pharmacology , Glycoproteins/genetics , Glycoproteins/metabolism , Humans , Jurkat Cells , Lectins, C-Type/metabolism , Models, Biological , Protein Binding , Receptors, Cell Surface/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , Viral Proteins/genetics , Viral Proteins/metabolism
10.
Viruses ; 12(12)2020 12 17.
Article in English | MEDLINE | ID: covidwho-979668

ABSTRACT

Viral entry is the first stage in the virus replication cycle and, for enveloped viruses, is mediated by virally encoded glycoproteins. Viral glycoproteins have different receptor affinities and triggering mechanisms. We employed vesicular stomatitis virus (VSV), a BSL-2 enveloped virus that can incorporate non-native glycoproteins, to examine the entry efficiencies of diverse viral glycoproteins. To compare the glycoprotein-mediated entry efficiencies of VSV glycoprotein (G), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S), Ebola (EBOV) glycoprotein (GP), Lassa (LASV) GP, and Chikungunya (CHIKV) envelope (E) protein, we produced recombinant VSV (rVSV) viruses that produce the five glycoproteins. The rVSV virions encoded a nano luciferase (NLucP) reporter gene fused to a destabilization domain (PEST), which we used in combination with the live-cell substrate EndurazineTM to monitor viral entry kinetics in real time. Our data indicate that rVSV particles with glycoproteins that require more post-internalization priming typically demonstrate delayed entry in comparison to VSV G. In addition to determining the time required for each virus to complete entry, we also used our system to evaluate viral cell surface receptor preferences, monitor fusion, and elucidate endocytosis mechanisms. This system can be rapidly employed to examine diverse viral glycoproteins and their entry requirements.


Subject(s)
Gene Expression , Genetic Vectors/genetics , Glycoproteins/genetics , Vesicular stomatitis Indiana virus/genetics , Viral Envelope Proteins/genetics , Virus Internalization , Animals , Cell Line , Chikungunya virus/genetics , Chlorocebus aethiops , Cloning, Molecular , Ebolavirus/genetics , Gene Order , Genes, Reporter , Humans , Lassa virus/genetics , SARS-CoV-2/genetics , Time Factors , Vero Cells , Virus Replication
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