scholarly journals Bafilomycin A1 and U18666A Efficiently Impair ZIKV Infection

Viruses ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 524 ◽  
Author(s):  
Catarina Sabino ◽  
Michael Basic ◽  
Daniela Bender ◽  
Fabian Elgner ◽  
Kiyoshi Himmelsbach ◽  
...  
Keyword(s):  
Life Cycle ◽  
Cholesterol Metabolism ◽  
Antiviral Effect ◽  
French Polynesia ◽  
Neurological Complications ◽  
Viral Life Cycle ◽  
Bafilomycin A1 ◽  
Atpase Inhibitor ◽  
Zikv Infection ◽  
Lysosomal Compartment

Zika virus (ZIKV) is a highly transmissive virus that belongs to the Flaviviridae family, which comprises several other pathogens that threaten human health. This re-emerging virus gained attention during the outbreak in Brazil in 2016, where a considerable number of microcephaly cases in newborns was associated with ZIKV infection during pregnancy. Lacking a preventive vaccine or antiviral drugs, efforts have been made to better understand the viral life cycle. In light of this, the relevance of the endosomal–lysosomal compartment for the ZIKV life cycle was investigated. A549 and SH-SY5Y cells were infected with either the African strain (associated with mild symptoms) or the French Polynesia strain (associated with neurological complications). For both strains, the V-ATPase inhibitor, bafilomycin A1, efficiently inhibited ZIKV entry and prevented the spread of the infection by interfering with viral maturation. Additionally, affecting cholesterol metabolism and transport with the drug U18666A, which inactivates late endosomes and lysosomes, impairs the viral life cycle. The data presented show a clear antiviral effect of two compounds that target the same compartments in different ways. This highlights the relevance of the endosomal–lysosomal compartment for the viral life cycle that should be considered as a target for antivirals.

scholarly journals Identification of the interferon-inducible GTPase GBP1 as major restriction factor for the Hepatitis E virus

2021 ◽  
Author(s):  
Mirco Glitscher ◽  
Kiyoshi Himmelsbach ◽  
Kathrin Woytinek ◽  
Anja Schollmeier ◽  
Reimar Johne ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Life Cycle ◽  
Defense Mechanism ◽  
Binding Protein ◽  
Public Health Problem ◽  
Antiviral Effect ◽  
Viral Life Cycle ◽  
Restriction Factor ◽  
Lysosomal Compartment ◽  
Guanylate Binding Protein

This study aims to gain deeper insight into HEV-induced innate immunity by characterizing the crosstalk between the virus and the host factor guanylate-binding protein 1 (GBP1). We observe that the amount of GBP1 is elevated upon infection, although number of transcripts is decreased, which is explained by a prolonged protein half-life. Modulation of GBP1 levels via overexpression significantly inhibits the viral life cycle. Use of various GBP-1 mutants revealed that the antiviral effect of GBP-1 on HEV is independent from the GTPase-activity, but depends on the capacity of GBP-1 to form GBP1 homodimers. This connects GBP-1 to the autophagosomal pathway. Indeed, dimerization competent GBP1 targets the viral capsid protein to the lysosomal compartment leading to inactivation of the viral particle. Most importantly, silencing of GBP1 abolishes the antiviral effect of IFNγ on HEV. In IFNγ treated cells the virus is targeted to lysosomal structures and destroyed therein. This process depends in part on GBP1. These observations about the relevance of GBP1 for type II interferon-mediated innate immunity against HEV could be a base for tailoring novel antivirals and improvement of disease management. IMPORTANCE Although HEV represents a worldwide public health problem with 20 million infections and 44.000 death cases per year, there are still no specific antivirals available and many aspects of the viral life cycle are not well understood. Here we identify the guanylate binding protein 1 (GBP1) as a restriction factor affecting life cycle of HEV. Surprisingly, the antiviral effect of GBP1 does not depend on its GTPase function, but on its capacity to homodimerize. We revealed that GBP1 exerts its antiviral activity by targeting HEV to the lysosomal compartment where the virus is inactivated. Most importantly, we observed that the antiviral effect of interferon-γ on HEV strongly depends on GBP1. Our observation that GBP1 impairs HEV and is crucial for the antiviral effect of interferons on HEV extends understanding of host defense-mechanisms. As the interferon-system represents a universal defense-mechanism, our study could help to design novel antivirals targeting.

The epidermal growth factor receptor is a relevant host factor in the early stages of Zika virus life cycle in vitro

2021 ◽  
Author(s):  
Catarina Sabino ◽  
Daniela Bender ◽  
Marie-Luise Herrlein ◽  
Eberhard Hildt
Keyword(s):  
Life Cycle ◽  
Zika Virus ◽  
A549 Cells ◽  
Growth Factor Receptor ◽  
Viral Life Cycle ◽  
Infection Process ◽  
Zikv Infection ◽  
Early Stages ◽  
Egfr Expression

Zika virus (ZIKV) is a flavivirus well-known for the epidemic in the Americas in 2015-2016, where microcephaly in newborns and other neurological complications were connected to ZIKV infection. Many aspects of the viral life cycle, including binding and entry into the host cell, are still enigmatic. Based on the observation that CHO cells lack the expression of EGFR and are not permissive for various ZIKV strains, the relevance of EGFR for the viral life cycle was analyzed. Infection of A549 cells by ZIKV leads to a rapid internalization of EGFR that colocalizes with the endosomal marker EEA1. Moreover, the infection by different ZIKV strains is associated with an activation of EGFR and subsequent activation of the MAPK/ERK signaling cascade. However, treatment of the cells with MβCD, which on the one hand leads to an activation of EGFR but on the other hand prevents EGFR internalization, impairs ZIKV infection. Specific inhibition of EGFR or of the RAS-RAF-MEK-ERK signal transduction cascade hinders ZIKV infection by inhibition of ZIKV entry. In accordance to this, knockout of EGFR expression impedes ZIKV entry. In case of an already established infection, inhibition of EGFR or of downstream signaling does not affect viral replication. Taken together, these data demonstrate the relevance of EGFR in the early stages of ZIKV infection and identify EGFR as a target for antiviral strategies. Importance These data deepen the knowledge about the ZIKV infection process and demonstrate the relevance of EGFR for ZIKV entry. In light of the fact that a variety of specific and efficient inhibitors of EGFR and of EGFR-dependent signaling were developed and licensed, repurposing of these substances could be a helpful tool to prevent the spreading of ZIKV infection in an epidemic outbreak.

scholarly journals Guillain-Barré syndrome associated with the Zika virus outbreak in Brazil

2016 ◽  
Vol 74 (3) ◽  
pp. 253-255 ◽  
Author(s):  
Lucas Masiêro Araujo ◽  
Maria Lucia Brito Ferreira ◽  
Osvaldo JM Nascimento
Keyword(s):  
Zika Virus ◽  
French Polynesia ◽  
Neurological Complications ◽  
Standard Test ◽  
Guillain Barre Syndrome ◽  
Zikv Infection ◽  
Resource Limited ◽  
Guillain Barré Syndrome ◽  
Large Outbreak ◽  
Guillain Barré

ABSTRACT Zika virus (ZIKV) is now considered an emerging flavivirosis, with a first large outbreak registered in the Yap Islands in 2007. In 2013, a new outbreak was reported in the French Polynesia, with associated cases of neurological complications including Guillain-Barré syndrome (GBS). The incidence of GBS has increased in Brazil since 2015, what is speculated to be secondary to the ZIKV infection outbreak. The gold-standard test for detection of acute ZIKV infection is the polymerase-chain reaction technique, an essay largely unavailable in Brazil. The diagnosis of GBS is feasible even in resource-limited areas using the criteria proposed by the GBS Classification Group, which is based solely on clinical grounds. Further understanding on the relationship of ZIKV with neurological complications is a research urgency.

scholarly journals Neurological manifestations of Chikungunya and Zika infections

2016 ◽  
Vol 74 (11) ◽  
pp. 937-943 ◽  
Author(s):  
Talys J. Pinheiro ◽  
Luis F. Guimarães ◽  
Marcus Tulius T. Silva ◽  
Cristiane N. Soares
Keyword(s):  
Clinical Picture ◽  
Transverse Myelitis ◽  
French Polynesia ◽  
Pulse Therapy ◽  
Neurological Complications ◽  
Guillain Barre Syndrome ◽  
Zikv Infection ◽  
Guillain Barré Syndrome ◽  
Atypical Manifestations ◽  
Guillain Barré

ABSTRACT The epidemics of Chikungunya virus (CHIKV) and Zika virus (ZIKV) infections have been considered the most important epidemiological occurrences in the Americas. The clinical picture of CHIKV infection is characterized by high fever, exanthema, myalgia, headaches, and arthralgia. Besides the typical clinical picture of CHIKV, atypical manifestations of neurological complications have been reported: meningo-encephalitis, meningoencephalo-myeloradiculitis, myeloradiculitis, myelitis, myeloneuropathy, Guillain-Barré syndrome and others. The diagnosis is based on clinical, epidemiological, and laboratory criteria. The most common symptoms of ZIKV infection are skin rash (mostly maculopapular), fever, arthralgia, myalgia, headache, and conjunctivitis. Some epidemics that have recently occurred in French Polynesia and Brazil, reported the most severe conditions, with involvement of the nervous system (Guillain-Barré syndrome, transverse myelitis, microcephaly and meningitis). The treatment for ZIKV and CHIKV infections are symptomatic and the management for neurological complications depends on the type of affliction. Intravenous immunoglobulin, plasmapheresis, and corticosteroid pulse therapy are options.

scholarly journals Nucleosome Positioning on Episomal Human Papillomavirus DNA in Cultured Cells

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 772
Author(s):  
Isao Murakami ◽  
Takashi Iwata ◽  
Tohru Morisada ◽  
Kyoko Tanaka ◽  
Daisuke Aoki
Keyword(s):  
Life Cycle ◽  
Cultured Cells ◽  
Basal Layer ◽  
Nucleosome Positioning ◽  
Viral Life Cycle ◽  
Human Papillomaviruses ◽  
Host Cells ◽  
Micrococcal Nuclease ◽  
Hpv Dna ◽  
Dna Replication And Repair

Several human papillomaviruses (HPV) are associated with the development of cervical carcinoma. HPV DNA synthesis is increased during the differentiation of infected host keratinocytes as they migrate from the basal layer of the epithelium to the spinous layer, but the molecular mechanism is unclear. Nucleosome positioning affects various cellular processes such as DNA replication and repair by permitting the access of transcription factors to promoters to initiate transcription. In this study, nucleosome positioning on virus chromatin was investigated in normal immortalized keratinocytes (NIKS) stably transfected with HPV16 or HPV18 genomes to determine if there is an association with the viral life cycle. Micrococcal nuclease-treated DNA analyzed by Southern blotting using probes against HPV16 and HPV18 and quantified by nucleosome scanning analysis using real-time PCR revealed mononucleosomal-sized fragments of 140–200 base pairs that varied in their location within the viral genome according to whether the cells were undergoing proliferation or differentiation. Notably, changes in the regions around nucleotide 110 in proliferating and differentiating host cells were common to HPV16 and HPV18. Our findings suggest that changes in nucleosome positions on viral DNA during host cell differentiation is an important regulatory event in the viral life cycle.

scholarly journals A Comprehensive, Flexible Collection of SARS-CoV-2 Coding Regions

2020 ◽  
Vol 10 (9) ◽  
pp. 3399-3402 ◽  
Author(s):  
Dae-Kyum Kim ◽  
Jennifer J Knapp ◽  
Da Kuang ◽  
Aditya Chawla ◽  
Patricia Cassonnet ◽  
...  
Keyword(s):  
Life Cycle ◽  
Viral Life Cycle ◽  
Coding Sequences ◽  
Coding Regions ◽  
Global Pandemic ◽  
The World ◽  
Molecular Studies ◽  
Widespread Availability ◽  
Rapid Transfer

Abstract The world is facing a global pandemic of COVID-19 caused by the SARS-CoV-2 coronavirus. Here we describe a collection of codon-optimized coding sequences for SARS-CoV-2 cloned into Gateway-compatible entry vectors, which enable rapid transfer into a variety of expression and tagging vectors. The collection is freely available. We hope that widespread availability of this SARS-CoV-2 resource will enable many subsequent molecular studies to better understand the viral life cycle and how to block it.

scholarly journals Retrograde Transport from the Pre-Golgi Intermediate Compartment and the Golgi Complex Is Affected by the Vacuolar H+-ATPase Inhibitor Bafilomycin A1

1998 ◽  
Vol 9 (12) ◽  
pp. 3561-3578 ◽  
Author(s):  
Harri Palokangas ◽  
Ming Ying ◽  
Kalervo Väänänen ◽  
Jaakko Saraste
Keyword(s):  
Brefeldin A ◽  
Retrograde Transport ◽  
Small Gtpase ◽  
Bafilomycin A1 ◽  
Atpase Inhibitor ◽  
Marker Proteins ◽  
Golgi Region ◽  
Intermediate Compartment ◽  
Acidic Compartments

The effect of the vacuolar H+-ATPase inhibitor bafilomycin A1 (Baf A1) on the localization of pre-Golgi intermediate compartment (IC) and Golgi marker proteins was used to study the role of acidification in the function of early secretory compartments. Baf A1 inhibited both brefeldin A- and nocodazole-induced retrograde transport of Golgi proteins to the endoplasmic reticulum (ER), whereas anterograde ER-to-Golgi transport remained largely unaffected. Furthermore, p58/ERGIC-53, which normally cycles between the ER, IC, and cis-Golgi, was arrested in pre-Golgi tubules and vacuoles, and the number of p58-positive ∼80-nm Golgi (coatomer protein I) vesicles was reduced, suggesting that the drug inhibits the retrieval of the protein from post-ER compartments. In parallel, redistribution of β-coatomer protein from the Golgi to peripheral pre-Golgi structures took place. The small GTPase rab1p was detected in short pre-Golgi tubules in control cells and was efficiently recruited to the tubules accumulating in the presence of Baf A1. In contrast, these tubules showed no enrichment of newly synthesized, anterogradely transported proteins, indicating that they participate in retrograde transport. These results suggest that the pre-Golgi structures contain an active H+-ATPase that regulates retrograde transport at the ER–Golgi boundary. Interestingly, although Baf A1 had distinct effects on peripheral pre-Golgi structures, only more central, p58-containing elements accumulated detectable amounts of 3-(2,4-dinitroanilino)-3′-amino-N-methyldipropylamine (DAMP), a marker for acidic compartments, raising the possibility that the lumenal pH of the pre-Golgi structures gradually changes in parallel with their translocation to the Golgi region.

scholarly journals Roles of the Picornaviral 3C Proteinase in the Viral Life Cycle and Host Cells

Viruses ◽  
2016 ◽  
Vol 8 (3) ◽  
pp. 82 ◽  
Author(s):  
Di Sun ◽  
Shun Chen ◽  
Anchun Cheng ◽  
Mingshu Wang
Keyword(s):  
Life Cycle ◽  
Viral Life Cycle ◽  
Host Cells

scholarly journals AdEasy-based cloning system to generate tropism expanded replicating adenoviruses expressing transgenes late in the viral life cycle

Gene Therapy ◽  
2005 ◽  
Vol 12 (17) ◽  
pp. 1347-1352 ◽  
Author(s):  
M Lie-A-Ling ◽  
C T Bakker ◽  
J G Wesseling ◽  
P J Bosma
Keyword(s):  
Life Cycle ◽  
Viral Life Cycle ◽  
Cloning System
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