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The liver X receptor agonist LXR 623 restricts flavivirus replication.

The vector-borne flaviviruses (VBFVs) are well known for causing great misery and death in humans worldwide. The VBFVs include those transmitted by mosquitos, such as Zika virus (ZIKV), dengue virus; and those transmitted by ticks including the tick-borne flavivirus serocomplex and Powassan virus (POWV). Two of our recent reports showed that intracranial POWV infection in the reservoir host, Peromyscus leucopus, was restricted and caused no overt clinical disease. Several modes of analyses suggested activation of the LXR pathway. Activation of the LXR pathway leads to increased efflux of chole…

Broad-Spectrum Flavivirus Inhibitors: a Medicinal Chemistry Point of View.

Infections by flaviviruses, such as Dengue, West Nile, Yellow Fever and Zika viruses, represent a growing risk for global health. There are vaccines only for few flaviviruses while no effective treatments are available. Flaviviruses share epidemiological, structural, and ecologic features and often different viruses can co-infect the same host. Therefore, the identification of broad-spectrum inhibitors is highly desirable either for known flaviviruses or for viruses that likely will emerge in the future. Strategies targeting both virus and host factors have been pursued to identify broad-spect…

Transcriptomic immune profiles of human flavivirus-specific T-cell responses.

The Flavivirus genus of viruses includes dengue (DENV), Zika (ZIKV), yellow fever (YFV), Japanese encephalitis (JEV), and West Nile (WNV) viruses. Infections with these species combined are prevalent in tropical and sub-tropical areas, affecting millions of people and ranging from asymptomatic to severe forms of the disease. They therefore pose a serious threat to global public health. Several studies imply a role for T cells in the protection but also pathogenesis against the different flavivirus species. Identifying flavivirus-specific T-cell immune profiles and determining how pre-exposure …

A high-throughput multiplex assay to characterize flavivirus-specific immunoglobulins.

Genus Flavivirus, which includes 53 virus species, is the leading cause of arthropod-borne diseases in humans. Diagnosis of these viral diseases is complicated by their overlapping epidemiology and clinical manifestations, and the fact that cross-reactive antibody responses are frequently elicited by individuals in response to infection. We developed a bead-based immunoassay to concomitantly profile the isotype and subclass of antibody responses (five isotypes and four subclasses) in parallel with specificity against multiple antigens. Our panel included 22 envelope (E) and non-structural 1 (N…

Screening Pipeline for Flavivirus Based Inhibitors for Zika Virus NS1.

In-silico pipeline is applied for identifying and designing novel inhibitors against ZIKV NS1 protein. Comparative molecular docking studies are performed to explore the binding of structurally diverse compounds to ZIKV NS1 by AutoDock/Vina and GOLD. The Zika virus (ZIKV) is a flavivirus, responsible for life-threatening infections and transmitted by Aedes mosquitoes in other organisms. It is associated with Guillain Barre Syndrome (GBS) and microcephaly. This epidemic increase in GBS and microcephaly convoyed the World Health Organization to affirm ZIKV a public health crisis. To combat the Z…

Wolbachia enhances insect-specific flavivirus infection in Aedes aegypti mosquitoes.

Mosquitoes transmit a diverse group of human flaviviruses including West Nile, dengue, yellow fever, and Zika viruses. Mosquitoes are also naturally infected with insect-specific flaviviruses (ISFs), a subgroup of the family not capable of infecting vertebrates. Although ISFs are not medically important, they are capable of altering the mosquito's susceptibility to flaviviruses and may alter host fitness. Wolbachia is an endosymbiotic bacterium of insects that when present in mosquitoes limits the replication of co-infecting pathogens, including flaviviruses. Artificially created Wolbachia-inf…

Review of diagnostic plaque reduction neutralization tests for flavivirus infection.

Flavivirus infections (including Japanese encephalitis, West Nile encephalitis and dengue fever/severe dengue) present a worldwide public health problem. Recent climate change may affect the geographical distribution of the arthropod vectors for these viruses and so the risk of flavivirus epidemics may increase. Many methods have been developed for the serological diagnosis of flavivirus infections, such as haemagglutination inhibition assay, enzyme-linked immunosorbent assay, and immunofluorescence in staining. However, the specificity of these assays varies. The plaque reduction neutralizing…

Mutational analysis of the zippering reaction during flavivirus membrane fusion.

The current model of flavivirus membrane fusion is based on atomic structures of truncated forms of the viral fusion protein E in its dimeric prefusion and trimeric postfusion conformations. These structures lack the two transmembrane domains (TMDs) of E as well as the so-called stem, believed to be involved in an intra- and intermolecular zippering reaction within the E trimer during the fusion process. In order to gain experimental evidence for the functional role of the stem in flavivirus membrane fusion, we performed a mutagenesis study with recombinant subviral particles (RSPs) of tick-bo…

Combinatorial computational approaches to identify tetracycline derivatives as flavivirus inhibitors.

Limited structural information of drug targets, cellular toxicity possessed by lead compounds, and large amounts of potential leads are the major issues facing the design-oriented approach of discovering new leads. In an attempt to tackle these issues, we have developed a process of virtual screening based on the observation that conformational rearrangements of the dengue virus envelope protein are essential for the mediation of viral entry into host cells via membrane fusion. Screening was based solely on the structural information of the Dengue virus envelope protein and was focused on a ta

Проверить механизм синтеза флавивирусной мембраны с помощью моноклонных антител.

В этом исследовании мы изучили в флавивирусной модели (вирус энцефалита, передаваемый током) механизмы ингибирования синтеза моноклональными антителами, направленные на различные области синтеза белка (E) и на различные участки в каждой из этих областей с помощью анализа in vitro. Наши данные свидетельствуют о том, что в зависимости от местоположения их связующих участков моноклонные антитела нарушаются на ранних или поздних этапах процесса синтеза, блокируя первоначальное взаимодействие с мембраной цели или вмешиваясь в надлежащее формирование структуры после синтеза Е, соответственно. Эти да

Совпадение в аннотации оригинала
In this study, we investigated in a flavivirus model (tick-borne encephalitis virus) the mechanisms of fusion inhibition by monoclonal antibodies directed to the different domains of the fusion protein (E) and to different sites within each of the domains by using in vitro fusion assays. Our data indicate that, depending on the location of their binding site…

Recent advances in flavivirus antiviral drug discovery and vaccine development.

Many flaviviruses, including yellow fever virus, dengue virus, Japanese encephalitis virus, tick-borne encephalitis virus, and West Nile virus, are globally important human pathogens. Despite an emergence and resurgence of flavivirus-mediated disease, specific therapies are not yet available; however, significant progress has been made toward the prevention and treatment of flavivirus infections. In this article we review recent advances made in the areas of (i) flavivirus vaccine development, and (ii) antiflavivirus drug discovery reported in literature and patents, and highlight strategies u…

West Nile Flavivirus Polioencephalomyelitis in a harbor seal (Phoca vitulina).

A 12-year-old male harbor seal presented with progressive signs of neurologic dysfunction including head tremors, muzzle twitching, clonic spasms, and weakness. Lesions included polioencephalomyelitis with glial nodules, spheroids, neuronophagia, ring hemorrhages, and a few neutrophils. Neurons, fibers, and glial nodules were multifocally colonized with intracytoplasmic West Nile flavivirus antigens that were demonstrated using indirect immunohistochemical analysis. Flavivirus on cultured cells also was isolated and was identified by use of monoclonal antibodies and reverse transcriptase-polym…

Flavivirus immunization with capsid-deletion mutants: basics, benefits, and barriers.

The flaviviruses comprise a number of arthropod-transmitted human disease agents that cause significant and increasing health threats in major parts of the world. The development of new vaccines is of vital importance, but the stringent need for safety, efficacy and cost-effectiveness together with the problems associated with the specific immune pathogenesis of some flavivirus infections impose significant challenges to innovative vaccine research. Using tick-borne encephalitis virus (TBEV) as a model, the viral capsid protein gene was recently identified as a novel target for generating flav…

Langat flavivirus protease NS3 binds caspase-8 and induces apoptosis.

The flavivirus NS3 protein plays an important role in the cleavage and processing of the viral polyprotein and in the synthesis of the viral RNA. NS3 recruits NS2B and NS5 proteins to form complexes possessing protease and replicase activities through protease and nucleoside triphosphatase/helicase domains. We have found that NS3 also induces apoptosis. Expression of the Langat (LGT) virus NS3 protein resulted in a cleavage of cellular DNA and reduced the viability of cells. Coexpression of NS3 with apoptotic inhibitors (CrmA and P35) and addition of caspase peptide substrates (Z-VAD-FMK and Z…

Enhanced neutralization of flavivirus by monoclonal antibodies against Negishi virus.

Ten monoclonal antibodies against Negishi virus were classified into 3 groups and 7 types according to the reaction patterns to Negishi virus by the hemagglutination inhibition (HI) test and by several kinds of neutralization tests. When kinetic neutralization was applied to these monoclonal antibodies at the same HI titer of 1:64, the initial slope and the persistent fraction of the kinetic curve was varied in each antibody. In the double-kinetic neutralization test, neutralization did not proceed further when the second antibody was the same type as the first one. When the second antibody wa

Antigenic characterization of flavivirus structural proteins separated by isoelectric focusing.

Isoelectrofocusing of nonionic-detergent-disrupted flaviviruses separated the envelope glycoprotein of 53,000 to 58,000 daltons and the nucleocapsid protein of 14,000 daltons. The envelope protein and nucleocapsid protein were isolated at isoelectric points of pI 7.8 and 10.3, respectively. The antigenic determinants of St. Louis encephalitis, Japanese encephalitis, and dengue virus envelope and nucleocapsid proteins were examined by solid-phase competition radioimmunoassay. By the appropriate selection of antiserum and competing proteins, it was possible to distinguish type-specific, complex-…

Environmental BPA exposure promotes flavivirus replication and extends mosquito lifespan.

Environmental exposure to endocrine-disrupting chemicals (EDCs) is widespread, yet their influence on arthropod-borne virus transmission rem … ly demonstrated. Our findings uncover a mechanism by which environmental BPA exposure may influence flavivirus transmission dynamics through redox modulation in mosquitoes, highlighting the need to incorporate pollutant impacts into arboviral risk assessments.

Dissecting the host determinants of flavivirus infection using QIC-seq.

Flaviviruses are genetically related, yet cause distinct disease patterns ranging from hepatitis and vascular shock syndrome to encephalitis and congenital abnormalities. There is an incomplete understanding of the cellular pathways co-opted by flaviviruses, and differences in host response to infection may underlie the diverse pathologies caused. We present a single-cell approach (Quantification of Infection and CRISPR guide sequencing; QIC-seq) that combines CRISPR/Cas9 knockout with virus-inclusive transcriptomics to systematically compare host factor requirements and host transcriptional r…

Atomic-resolution structure of a chimeric Powassan tick-borne flavivirus.

Powassan virus (POWV) is an emerging tick-borne flavivirus for which no vaccine or antiviral treatment exists. The incidence of human infections of POWV in North America has been increasing because of the expanding distribution of the tick vector Ixodes scapularis that transmits POWV to humans. To mitigate the dangers of handling a risk group 3 human pathogen, a chimeric virus was constructed from the genetic backbone of a yellow fever virus vaccine strain 17D (YFV-17D) and the external structural proteins of POWV lineage II. The chimera had a comparable phenotype as POWV. The atomic resolutio…

Dietary Patterns and Anti-Flavivirus IgG Seroconversion in Colombian Children.

The burden of flaviviral infections, especially dengue and Zika, is high in the Americas. Malnutrition affects the risk and response to infections, but the role of diet on flaviviral infection risk is uncertain. The objective of this study was to investigate the relations between dietary patterns adherence and anti-flavivirus IgG seroconversion in children during a Zika epidemic in a dengue-endemic area of Colombia. In 2015-2016, we followed 424 anti-flavivirus IgG seronegative children aged 2 to 12 years for 1 year. Baseline data included children's sociodemographic, anthropometric, and dieta…