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comprehensive mapping of common immunodominant epitopes in the west nile virus nonstructural protein 1 recognized by avian antibody responses.west nile virus (wnv) is a mosquito-borne flavivirus that primarily infects birds but occasionally infects humans and horses. certain species of birds, including crows, house sparrows, geese, blue jays and ravens, are considered highly susceptible hosts to wnv. the nonstructural protein 1 (ns1) of wnv can elicit protective immune responses, including ns1-reactive antibodies, during infection of animals. the antigenicity of ns1 suggests that ns1-reactive antibodies could provide a basis for serol ...201222347477
evolution of mosquito-based arbovirus surveillance systems in australia.control of arboviral disease is dependent on the sensitive and timely detection of elevated virus activity or the identification of emergent or exotic viruses. the emergence of japanese encephalitis virus (jev) in northern australia revealed numerous problems with performing arbovirus surveillance in remote locations. a sentinel pig programme detected jev activity, although there were a number of financial, logistical, diagnostic and ethical limitations. a system was developed which detected vir ...201222505808
west nile virus neurologic disease in humans, south africa, september 2008-may 2009.we investigated west nile virus (wnv) as a possible disease etiology in persons hospitalized in south africa. of 206 specimens tested, 36 had wnv neutralizing antibodies, significantly more than in similar earlier serosurveys. seven probable acute wnv cases were identified, suggesting wnv may be overlooked as an etiology of severe disease in south africa.201223171668
descriptive overview of the 2011 epidemic of arboviral disease in horses in australia.to provide an overview and descriptive analysis of the 2011 arboviral disease epidemic in horses that involved three important australian mosquito-borne viruses: murray valley encephalitis virus, west nile virus (kunjin strain) and ross river virus.201223356366
novel vaccine against venezuelan equine encephalitis combines advantages of dna immunization and a live attenuated vaccine.dna vaccines combine remarkable genetic and chemical stability with proven safety and efficacy in animal models, while remaining less immunogenic in humans. in contrast, live-attenuated vaccines have the advantage of inducing rapid, robust, long-term immunity after a single-dose vaccination. here we describe novel idna vaccine technology that is based on an infectious dna platform and combines advantages of dna and live attenuated vaccines. we applied this technology for vaccination against infe ...201223287629
etiology of acute, non-malaria, febrile illnesses in jayapura, northeastern papua, indonesia.abstract. we conducted a prospective, inpatient fever study in malaria-endemic papua, indonesia to determine non-malaria fever etiologies. investigations included malaria blood films, blood culture, paired serologic samples analysis for dengue, japanese encephalitis, leptospirosis, scrub typhus, murine typhus, and spotted fever group rickettsia. during 1997-2000, 226 patients (127 males and 99 females) 1-80 years of age (median age = 25 years) were enrolled. positive blood cultures (n = 34, 15%) ...201222232450
Uncoupling cis-Acting RNA Elements from Coding Sequences Revealed a Requirement of the N-Terminal Region of Dengue Virus Capsid Protein in Virus Particle Formation.Little is known about the mechanism of flavivirus genome encapsidation. Here, functional elements of the dengue virus (DENV) capsid (C) protein were investigated. Study of the N-terminal region of DENV C has been limited by the presence of overlapping cis-acting RNA elements within the protein-coding region. To dissociate these two functions, we used a recombinant DENV RNA with a duplication of essential RNA structures outside the C coding sequence. By the use of this system, the highly conserve ...201222072762
Comprehensive mapping of West Nile virus (WNV)- and Japanese encephalitis virus serocomplex-specific linear B-cell epitopes from WNV non-structural protein 1.West Nile virus (WNV) non-structural protein 1 (NS1) elicits protective immune responses during infection of animals. WNV NS1-specific antibody responses can provide the basis for serological diagnostic reagents, so the antigenic sites in NS1 that are targeted by host immune responses need to be identified and the conservation of these sites among the Japanese encephalitis virus (JEV) serocomplex members also needs to be defined. The present study describes the mapping of linear B-cell epitopes ...201221940411
Structural gene (prME) chimeras of St Louis encephalitis virus and West Nile virus exhibit altered in vitro cytopathic and growth phenotypes.Despite utilizing the same avian hosts and mosquito vectors, St Louis encephalitis virus (SLEV) and West Nile virus (WNV) display dissimilar vector-infectivity and vertebrate-pathogenic phenotypes. SLEV exhibits a low oral infection threshold for Culex mosquito vectors and is avirulent in avian hosts, producing low-magnitude viraemias. In contrast, WNV is less orally infective to mosquitoes and elicits high-magnitude viraemias in a wide range of avian species. In order to identify the genetic de ...201221940408
interplay between viruses and host mrna degradation.messenger rna degradation is a fundamental cellular process that plays a critical role in regulating gene expression by controlling both the quality and the abundance of mrnas in cells. naturally, viruses must successfully interface with the robust cellular rna degradation machinery to achieve an optimal balance between viral and cellular gene expression and establish a productive infection in the host. in the past several years, studies have discovered many elegant strategies that viruses have ...201223274304
a novel coding-region rna element modulates infectious dengue virus particle production in both mammalian and mosquito cells and regulates viral replication in aedes aegypti mosquitoes.dengue virus (denv) is an enveloped flavivirus with a positive-sense rna genome transmitted by aedes mosquitoes, causing the most important arthropod-borne viral disease affecting humans. relatively few cis-acting rna regulatory elements have been described in the denv coding-region. here, by introducing silent mutations into a denv-2 infectious clone, we identify the conserved capsid-coding region 1 (ccr1), an rna sequence element that regulates viral replication in mammalian cells and to a gre ...201222840606
the contribution of rodent models to the pathological assessment of flaviviral infections of the central nervous system.members of the genus flavivirus are responsible for a spectrum of important neurological syndromes in humans and animals. rodent models have been used extensively to model flavivirus neurological disease, to discover host-pathogen interactions that influence disease outcome, and as surrogates to determine the efficacy and safety of vaccines and therapeutics. in this review, we discuss the current understanding of flavivirus neuroinvasive disease and outline the host, viral and experimental facto ...201222592957
a physical interaction between viral replicase and capsid protein is required for genome-packaging specificity in an rna virus.genome packaging is functionally coupled to replication in rna viruses pathogenic to humans (poliovirus), insects (flock house virus [fhv]), and plants (brome mosaic virus [bmv]). however, the underlying mechanism is not fully understood. we have observed previously that in fhv and bmv, unlike ectopically expressed capsid protein (cp), packaging specificity results from rna encapsidation by cp that has been translated from mrna produced from replicating genomic rna. consequently, we hypothesize ...201222438552
current ebola vaccines.ebolaviruses cause severe viral hemorrhagic fever in humans and non-human primates (nhps), with case fatality rates of up to 90%. currently, neither a specific treatment nor a vaccine licensed for use in humans is available. however, a number of vaccine candidates have been developed in the last decade that are highly protective in nhps, the gold standard animal model for ebola hemorrhagic fever.201222559078
biogenesis and dynamics of the coronavirus replicative structures.coronaviruses are positive-strand rna viruses that are important infectious agents of both animals and humans. a common feature among positive-strand rna viruses is their assembly of replication-transcription complexes in association with cytoplasmic membranes. upon infection, coronaviruses extensively rearrange cellular membranes into organelle-like replicative structures that consist of double-membrane vesicles and convoluted membranes to which the nonstructural proteins involved in rna synthe ...201223202524
a three-dimensional comparison of tick-borne flavivirus infection in mammalian and tick cell lines.tick-borne flaviviruses (tbfv) are sustained in nature through cycling between mammalian and tick hosts. in this study, we used african green monkey kidney cells (vero) and ixodes scapularis tick cells (ise6) to compare virus-induced changes in mammalian and arthropod cells. using confocal microscopy, transmission electron microscopy (tem), and electron tomography (et), we examined viral protein distribution and the ultrastructural changes that occur during tbfv infection. within host cells, fla ...201223112871
new insights into control of arbovirus replication and spread by insect rna interference pathways.arthropod-borne (arbo) viruses are transmitted by vectors, such as mosquitoes, to susceptible vertebrates. recent research has shown that arbovirus replication and spread in mosquitoes is not passively tolerated but induces host responses to control these pathogens. small rna-mediated host responses are key players among these antiviral immune strategies. studies into one such small rna-mediated antiviral response, the exogenous rna interference (rnai) pathway, have generated a wealth of informa ...201226466541
west nile virus noncoding subgenomic rna contributes to viral evasion of the type i interferon-mediated antiviral response.we previously showed that a noncoding subgenomic flavivirus rna (sfrna) is required for viral pathogenicity, as a mutant west nile virus (wnv) deficient in sfrna production replicated poorly in wild-type mice. to investigate the possible immunomodulatory or immune evasive functions of sfrna, we utilized mice and cells deficient in elements of the type i interferon (ifn) response. replication of the sfrna mutant wnv was rescued in mice and cells lacking interferon regulatory factor 3 (irf-3) and ...201222379089
amp-activated kinase restricts rift valley fever virus infection by inhibiting fatty acid synthesis.the cell intrinsic innate immune responses provide a first line of defense against viral infection, and often function by targeting cellular pathways usurped by the virus during infection. in particular, many viruses manipulate cellular lipids to form complex structures required for viral replication, many of which are dependent on de novo fatty acid synthesis. we found that the energy regulator ampk, which potently inhibits fatty acid synthesis, restricts infection of the bunyavirus, rift valle ...201222532801
highly similar structural frames link the template tunnel and ntp entry tunnel to the exterior surface in rna-dependent rna polymerases.rna-dependent rna polymerase (rdrp) is essential to viral replication and is therefore one of the primary targets of countermeasures against these dangerous infectious agents. development of broad-spectrum therapeutics targeting polymerases has been hampered by the extreme sequence variability of these sequences. rdrps range in length from 400-800 residues, yet contain only ∼20 residues that are conserved in most species. in this study, we made structure-based comparisons that are independent of ...201223275546
a noncoding rna produced by arthropod-borne flaviviruses inhibits the cellular exoribonuclease xrn1 and alters host mrna stability.all arthropod-borne flaviviruses generate a short noncoding rna (sfrna) from the viral 3' untranslated region during infection due to stalling of the cellular 5'-to-3' exonuclease xrn1. we show here that formation of sfrna also inhibits xrn1 activity. cells infected with dengue or kunjin viruses accumulate uncapped mrnas, decay intermediates normally targeted by xrn1. xrn1 repression also resulted in the increased overall stability of cellular mrnas in flavivirus-infected cells. importantly, a m ...201223006624
characterization of west nile viruses isolated from captive american flamingoes (phoenicopterus ruber) in medellin, colombia.serum samples from a total of 71 healthy captive birds belonging to 18 species were collected in july of 2008 in medellin (colombia) and tested for flaviviruses. eighteen of 29 samples from american flamingoes (phoenicopterus ruber) were positive for west nile virus (wnv) by reverse transcription-polymerase chain reaction. selected positive samples were serially passaged and wnv was confirmed by immunofluorescence. two isolates (524/08, 9835/08) were characterized in vitro and in vivo. sequence ...201222802436
characterization of rabensburg virus, a flavivirus closely related to west nile virus of the japanese encephalitis antigenic group.rabensburg virus (rabv), a flavivirus with ∼76% nucleotide and 90% amino acid identity with representative members of lineage one and two west nile virus (wnv), previously was isolated from culex pipiens and aedes rossicus mosquitoes in the czech republic, and phylogenetic and serologic analyses demonstrated that it was likely a new lineage of wnv. however, no direct link between rabv and human disease has been definitively established and the extent to which rabv utilizes the typical wnv transm ...201222724010
diagnostic strategy used to establish etiologies of encephalitis in a prospective cohort of patients in england.the laboratory diagnostic strategy used to determine the etiology of encephalitis in 203 patients is reported. an etiological diagnosis was made by first-line laboratory testing for 111 (55%) patients. subsequent testing, based on individual case reviews, resulted in 17 (8%) further diagnoses, of which 12 (71%) were immune-mediated and 5 (29%) were due to infection. seventy-five cases were of unknown etiology. sixteen (8%) of 203 samples were found to be associated with either n-methyl-d-asparta ...201121865429
Reduced avian virulence and viremia of West Nile virus isolates from Mexico and Texas.A West Nile virus (WNV) isolate from Mexico (TM171-03) and BIRD1153, a unique genotype from Texas, have exhibited reduced murine neuroinvasive phenotypes. To determine if murine neuroinvasive capacity equates to avian virulence potential, American crow (Corvus brachyrhynchos) and house sparrows (Passer domesticus) were experimentally inoculated with representative murine neuroinvasive/non-neuroinvasive strains. In both avian species, a plaque variant from Mexico that was E-glycosylation competen ...201121976584
flavivirus ns3 and ns5 proteins interaction network: a high-throughput yeast two-hybrid screen.the genus flavivirus encompasses more than 50 distinct species of arthropod-borne viruses, including several major human pathogens, such as west nile virus, yellow fever virus, japanese encephalitis virus and the four serotypes of dengue viruses (denv type 1-4). each year, flaviviruses cause more than 100 million infections worldwide, some of which lead to life-threatening conditions such as encephalitis or haemorrhagic fever. among the viral proteins, ns3 and ns5 proteins constitute the major e ...201122014111
west nile virus replication requires fatty acid synthesis but is independent on phosphatidylinositol-4-phosphate lipids.west nile virus (wnv) is a neurovirulent mosquito-borne flavivirus, which main natural hosts are birds but it also infects equines and humans, among other mammals. as in the case of other plus-stranded rna viruses, wnv replication is associated to intracellular membrane rearrangements. based on results obtained with a variety of viruses, different cellular processes have been shown to play important roles on these membrane rearrangements for efficient viral replication. as these processes are re ...201121949814
identification of a functional, crm-1-dependent nuclear export signal in hepatitis c virus core protein.hepatitis c virus (hcv) infection is a major cause of chronic liver disease worldwide. hcv core protein is involved in nucleocapsid formation, but it also interacts with multiple cytoplasmic and nuclear molecules and plays a crucial role in the development of liver disease and hepatocarcinogenesis. the core protein is found mostly in the cytoplasm during hcv infection, but also in the nucleus in patients with hepatocarcinoma and in core-transgenic mice. hcv core contains nuclear localization sig ...201122039426
successful propagation of flavivirus infectious cdnas by a novel method to reduce the cryptic bacterial promoter activity of virus genomes.reverse genetics is a powerful tool to study single-stranded rna viruses. despite tremendous efforts having been made to improve the methodology for constructing flavivirus cdnas, the cause of toxicity of flavivirus cdnas in bacteria remains unknown. here we performed mutational analysis studies to identify escherichia coli promoter (ecp) sequences within nucleotides (nt) 1 to 3000 of the dengue virus type 2 (denv2) and japanese encephalitis virus (jev) genomes. eight and four active ecps were d ...201121228244
identification and characterization of the host protein dnajc14 as a broadly active flavivirus replication modulator.viruses in the flavivirus genus of the flaviviridae family are arthropod-transmitted and contribute to staggering numbers of human infections and significant deaths annually across the globe. to identify cellular factors with antiviral activity against flaviviruses, we screened a cdna library using an iterative approach. we identified a mammalian hsp40 chaperone protein (dnajc14) that when overexpressed was able to mediate protection from yellow fever virus (yfv)-induced cell death. further stud ...201121249176
seroprevalence of west nile virus in wild birds in far eastern russia using a focus reduction neutralization test.west nile (wn) virus has been spreading geographically to non-endemic areas in various parts of the world. however, little is known about the extent of wn virus infection in russia. japanese encephalitis (je) virus, which is closely related to wn virus, is prevalent throughout east asia. we evaluated the effectiveness of a focus reduction neutralization test in young chicks inoculated with je and wn viruses, and conducted a survey of wn infection among wild birds in far eastern russia. following ...201121363987
fuse binding protein 1 interacts with untranslated regions of japanese encephalitis virus rna and negatively regulates viral replication.the untranslated regions (utrs) located at the 5' and 3' ends of the japanese encephalitis virus (jev) genome, a positive-sense rna, are involved in viral translation, the initiation of rna synthesis, and the packaging of nascent virions. the cellular and viral proteins that participate in these processes are expected to interact with the utrs. in this study, we used biotinylated rna-protein pulldown and liquid chromatography-mass spectrometry/mass spectrometry (lc-ms/ms) analyses to identify th ...201121367899
identification of a conserved jev serocomplex b-cell epitope by screening a phage-display peptide library with a mab generated against west nile virus capsid protein.the west nile virus (wnv) capsid (c) protein is one of the three viral structural proteins, encapsidates the viral rna to form the nucleocapsid, and is necessary for nuclear and nucleolar localization. the antigenic sites on c protein that are targeted by humoral immune responses have not been studied thoroughly, and well-defined b-cell epitopes on the wnv c protein have not been reported.201121375771
stat2 mediates innate immunity to dengue virus in the absence of stat1 via the type i interferon receptor.dengue virus (denv) is a mosquito-borne flavivirus, and symptoms of infection range from asymptomatic to the severe dengue hemorrhagic fever/dengue shock syndrome (dhf/dss). high viral loads correlate with disease severity, and both type i & ii interferons (ifns) are crucial for controlling viral replication. we have previously reported that signal transducer and activator of transcription (stat) 1-deficient mice are resistant to denv-induced disease, but little is known about this stat1-indepen ...201121379341
assembly of alphavirus replication complexes from rna and protein components in a novel trans-replication system in mammalian cells.for positive-strand rna viruses, the viral genomic rna also acts as an mrna directing the translation of the replicase proteins of the virus. replication takes place in association with cytoplasmic membranes, which are heavily modified to create specific replication compartments. here we have expressed by plasmid dna transfection the large replicase polyprotein of semliki forest virus (sfv) in mammalian cells from a nonreplicating mrna and provided a separate rna containing the replication signa ...201121389137
the capsid-binding nucleolar helicase ddx56 is important for infectivity of west nile virus.recent findings suggest that in addition to its role in packaging genomic rna, the west nile virus (wnv) capsid protein is an important pathogenic determinant, a scenario that requires interaction of this viral protein with host cell proteins. we performed an extensive multitissue yeast two-hybrid screen to identify capsid-binding proteins in human cells. here we describe the interaction between wnv capsid and the nucleolar rna helicase ddx56/noh61. coimmunoprecipitation confirmed that capsid pr ...201121411523
virulence determinants between new york 99 and kunjin strains of west nile virus.an attenuated australian strain of west nile virus (wnv), kunjin (kun), shares ~98% amino acid homology with the pathogenic new york 99 ny99 strain (ny99). to investigate the viral factors involved in ny99 virulence we generated an infectious cdna clone of the wnv ny99 4132 isolate from which virus was recovered and was shown to be indistinguishable from the parental isolate. we then introduced the regions of the ny99 non-structural (ns) proteins and/or untranslated regions (utrs) into the kun b ...201121477835
identification of a cryptic prokaryotic promoter within the cdna encoding the 5' end of dengue virus rna genome.infectious cdna clones of rna viruses are important research tools, but flavivirus cdna clones have proven difficult to assemble and propagate in bacteria. this has been attributed to genetic instability and/or host cell toxicity, however the mechanism leading to these difficulties has not been fully elucidated. here we identify and characterize an efficient cryptic bacterial promoter in the cdna encoding the dengue virus (denv) 5' utr. following cryptic transcription in e. coli, protein express ...201121483867
delayed cytosolic exposure of japanese encephalitis virus double-stranded rna impedes interferon activation and enhances viral dissemination in porcine cells.interferon is a principal component of the host antiviral defense system. in this study, abortive focus formation by japanese encephalitis virus (jev) in primate cells was accompanied with early interferon induction, while productive focus formation in porcine cells was associated with a late interferon response. neutralization antibodies against interferon relieved the restricted infection in primate cells, and increasingly larger foci were generated as treatment with exogenous interferon was d ...201121525349
genetic characterization of west nile virus lineage 2, greece, 2010.we conducted a complete genome analysis of a west nile virus detected in culex pipiens mosquitoes during a severe outbreak of human west nile disease in greece 2010. the virus showed closest genetic relationship to the lineage 2 strain that emerged in hungary in 2004; increased virulence may be associated with amino acid substitution h249p.201121529413
defective interfering viral particles in acute dengue infections.while much of the genetic variation in rna viruses arises because of the error-prone nature of their rna-dependent rna polymerases, much larger changes may occur as a result of recombination. an extreme example of genetic change is found in defective interfering (di) viral particles, where large sections of the genome of a parental virus have been deleted and the residual sub-genome fragment is replicated by complementation by co-infecting functional viruses. while most reports of di particles h ...201121559384
[kunjin virus replicon--a novel viral vector].viral replicon is a kind of self-replicating viral rna sourced from viral genome, which contains viral non-structural genes that are critical for viral genome replication with structural proteins deleted or replaced by foreign genes. kunjin virus is a member of the flavivirida family, flavivirus genus, and kunjin virus replicon is the first and the clearly defined flavivirus replicon. kunjun virus replicon has been regarded as an excellent viral vector on account of its high expression, lower cy ...201121650037
pdna-lipoplexes engrafted with flagellin-related peptide induce potent immunity and anti-tumour effects.complexes of cationic lipids and dna (lipoplexes) are widely used for non-viral gene delivery and dna vaccine development, but cationic lipids are toxic and promote non-specific interactions with cells, leading to poor efficacy. near-neutral lipoplexes, on the other hand, can obviate toxicity, but a convenient means to target them to specific cells such as dendritic cells (dcs) has been lacking. here, we show that a his-tagged flagellin-derived peptide (denoted 9flg), previously reported to prom ...201121798298
genotype v japanese encephalitis virus is emerging.japanese encephalitis (je) is a global public health issue that has spread widely to more than 20 countries in asia and has extended its geographic range to the south pacific region including australia. je has become the most important cause of viral encephalitis in the world. japanese encephalitis viruses (jev) are divided into five genotypes, based on the nucleotide sequence of the envelope (e) gene. the muar strain, isolated from patient in malaya in 1952, is the sole example of genotype v je ...201121750744
identification of two linear b-cell epitopes from west nile virus ns1 by screening a phage-displayed random peptide library.abstract:201121729328
a conserved peptide in west nile virus ns4a protein contributes to proteolytic processing and is essential for replication.the west nile virus strain kunjin virus (wnv(kun)) ns4a protein is a multifunctional protein involved in membrane proliferation, stimulation of cellular pathways, and evasion of host defense and is a major component of the wnv(kun) rna replication complex. we identified a highly conserved region ((120)p-e-p-e(123)) upstream of the viral protease dibasic cleavage site and investigated whether this motif was required for wnv(kun) replication. single point mutations to alanine and a pepe deletion m ...201121880777
west nile virus population genetics and evolution.west nile virus (wnv) (flaviviridae: flavivirus) is transmitted from mosquitoes to birds, but can cause fatal encephalitis in infected humans. since its introduction into north america in new york in 1999, it has spread throughout the western hemisphere. multiple outbreaks have also occurred in europe over the last 20 years. this review highlights recent efforts to understand how host pressures impact viral population genetics, genotypic and phenotypic changes which have occurred in the wnv geno ...201122226703
novel flaviviruses detected in different species of mosquitoes in spain.abstract we report the characterization of three novel flaviviruses isolated in spain. marisma mosquito virus, a novel mosquito borne virus, was isolated from ochlerotatus caspius mosquitoes; spanish ochlerotatus flavivirus and spanish culex flavivirus, two novel insect flaviviruses, were isolated from oc. caspius and culex pipiens, respectively. during this investigation, we designed a sensitive rt-nested polymerase chain reaction method that amplifies a 1019bp fragment of the flavivirus ns5 ...201122022811
west nile virus (kunjin subtype) disease in the northern territory of australia--a case of encephalitis and review of all reported cases.west nile virus kunjin subtype (wnv/kunv) is enzootic across the tropical north of australia, with epizootic spread into other jurisdictions. the clinical spectrum of illness in humans is poorly described. we report a clinical case of wnv/kunv encephalitis and performed a retrospective chart audit of all cases of wnv/kunv notified in the northern territory from 1992 to 2010. thirteen cases of wnv/kunv disease were identified; case notes were available for 10 of these presentations. six of these ...201122049056
small noncoding rna modulates japanese encephalitis virus replication and translation in trans.sequence and structural elements in the 3'-untranslated region (utr) of japanese encephalitis virus (jev) are known to regulate translation and replication. we previously reported an abundant accumulation of small subgenomic flaviviral rna (sfrna) which is collinear with the highly conserved regions of the 3'-utr in jev-infected cells. however, function of the sfrna in jev life cycle remains unknown.201122040380
the role of interferon antagonist, non-structural proteins in the pathogenesis and emergence of arboviruses.a myriad of factors favor the emergence and re-emergence of arthropod-borne viruses (arboviruses), including migration, climate change, intensified livestock production, an increasing volume of international trade and transportation, and changes to ecosystems (e.g., deforestation and loss of biodiversity). consequently, arboviruses are distributed worldwide and represent over 30% of all emerging infectious diseases identified in the past decade. although some arboviral infections go undetected o ...201121994750
Tembusu virus in ducks, china.In China in 2010, a disease outbreak in egg-laying ducks was associated with a flavivirus. The virus was isolated and partially sequenced. The isolate exhibited 87%-91% identity with strains of Tembusu virus, a mosquito-borne flavivirus of the Ntaya virus group. These findings demonstrate emergence of Tembusu virus in ducks.201122000358
Globalization, land use, and the invasion of West Nile virus.Many invasive species that have been spread through the globalization of trade and travel are pathogens. A paradigmatic case is the introduction of West Nile virus (WNV) into North America in 1999. A decade of research on the ecology and evolution of WNV includes three findings that provide insight into the outcome of future pathogen introductions. First, WNV transmission in North America is highest in urbanized and agricultural habitats, in part because the hosts and vectors of WNV are abundant ...201122021850
heterogeneous nuclear ribonucleoprotein a2 participates in the replication of japanese encephalitis virus through an interaction with viral proteins and rna.japanese encephalitis virus (jev) is a mosquito-borne flavivirus that is kept in a zoonotic transmission cycle between pigs and mosquitoes. jev causes infection of the central nervous system with a high mortality rate in dead-end hosts, including humans. many studies have suggested that the flavivirus core protein is not only a component of nucleocapsids but also an important pathogenic determinant. in this study, we identified heterogeneous nuclear ribonucleoprotein a2 (hnrnp a2) as a binding p ...201121865391
kunjin virus replicon-based vaccines expressing ebola virus glycoprotein gp protect the guinea pig against lethal ebola virus infection.pre- or postexposure treatments against the filoviral hemorrhagic fevers are currently not available for human use. we evaluated, in a guinea pig model, the immunogenic potential of kunjin virus (kun)-derived replicons as a vaccine candidate against ebola virus (ebov). virus like particles (vlps) containing kun replicons expressing ebov wild-type glycoprotein gp, membrane anchor-truncated gp (gp/ctr), and mutated gp (d637l) with enhanced shedding capacity were generated and assayed for their pro ...201121987742
the cell biology of the unfolded protein response.the unfolded protein response (upr) is an ensemble of signal transduction pathways that respond to perturbations in the oxidative, pro-folding environment of the endoplasmic reticulum. during the past decade, ongoing research implicated these pathways in maintaining homeostasis of cells and organisms exposed to various stresses. herein, we highlight recent findings regarding the functional role of the upr in both normal and pathophysiologic processes.201121620842
reverse genetic analysis of ourmiaviruses reveals the nucleolar localization of the coat protein in nicotiana benthamiana and unusual requirements for virion formation.ourmia melon virus (oumv) is the type member of the genus ourmiavirus. these viruses have a trisegmented genome, each part of which encodes a single protein. ourmiaviruses share a distant similarity with other plant viruses only in their movement proteins (mp), whereas their rna-dependent rna polymerase (rdrp) shares features only with fungal viruses of the family narnaviridae. thus, ourmiaviruses are in a unique phylogenetic position among existing plant viruses. here, we developed an agroinocu ...201121411534
should there be a standardised approach to the diagnostic workup of suspected adult encephalitis? a case series from australia.the clinical diagnosis of encephalitis is often difficult and identification of a causative organism is infrequent. the encephalitis syndrome may herald the emergence of novel pathogens with outbreak potential. individual treatment and an effective public health response rely on identifying a specific pathogen. in australia there have been no studies to try to improve the identification rate of encephalitis pathogens. this study aims to review the diagnostic assessment of adult suspected encepha ...201021159185
rna replicons - a new approach for influenza virus immunoprophylaxis.rna replicons are derived from either positive- or negative-strand rna viruses. they represent disabled virus vectors that are not only avirulent, but also unable to revert to virulence. due to autonomous rna replication, rna replicons are able to drive high level, cytosolic expression of recombinant antigens stimulating both the humoral and the cellular branch of the immune system. this review provides an update on the available literature covering influenza virus vaccines based on rna replicon ...201021994644
lipid metabolism and hcv infection.chronic infection by hepatitis c virus (hcv) can lead to severe liver disease and is a global healthcare problem. the liver is highly metabolically active and one of its key functions is to control the balance of lipid throughout the body. a number of pathologies have been linked to the impact of hcv infection on liver metabolism. however, there is also growing evidence that hepatic metabolic processes contribute to the hcv life cycle. this review summarizes the relationship between lipid metabo ...201021994676
how flaviviruses activate and suppress the interferon response.the flavivirus genus includes viruses with a remarkable ability to produce disease on a large scale. the expansion and increased endemicity of dengue and west nile viruses in the americas exemplifies their medical and epidemiological importance. the rapid detection of viral infection and induction of the innate antiviral response are crucial to determining the outcome of infection. the intracellular pathogen receptors rig-i and mda5 play a central role in detecting flavivirus infections and init ...201021994652
identification of gbf1 as a cellular factor required for hepatitis c virus rna replication.in infected cells, hepatitis c virus (hcv) induces the formation of membrane alterations referred to as membranous webs, which are sites of rna replication. in addition, hcv rna replication also occurs in smaller membrane structures that are associated with the endoplasmic reticulum. however, cellular mechanisms involved in the formation of hcv replication complexes remain largely unknown. here, we used brefeldin a (bfa) to investigate cellular mechanisms involved in hcv infection. bfa acts on c ...201019906930
structure and functionality in flavivirus ns-proteins: perspectives for drug design.flaviviridae are small enveloped viruses hosting a positive-sense single-stranded rna genome. besides yellow fever virus, a landmark case in the history of virology, members of the flavivirus genus, such as west nile virus and dengue virus, are increasingly gaining attention due to their re-emergence and incidence in different areas of the world. additional environmental and demographic considerations suggest that novel or known flaviviruses will continue to emerge in the future. nevertheless, u ...201019945487
establishment of one-step sybr green-based real time-pcr assay for rapid detection and quantification of chikungunya virus infection.chikungunya virus (chikv) is a mosquito-borne alphavirus and one of the prevalent re-emerging arbovirus in tropical and subtropical regions of asia, africa, and central and south america. it produces a spectrum of illness ranging from inapparent infection to moderate febrile illness as well as severe arthralgia or arthritis affecting multiple joints. in this study, a quantitative, one-step real-time sybr green-based rt-pcr system for the non-structural protein 2 (nsp2) of chikv that can quantify ...201020092632
evidence for ribosomal frameshifting and a novel overlapping gene in the genomes of insect-specific flaviviruses.flaviviruses have a positive-sense, single-stranded rna genome of approximately 11 kb, encoding a large polyprotein that is cleaved to produce approximately 10 mature proteins. cell fusing agent virus, kamiti river virus, culex flavivirus and several recently discovered flaviviruses have no known vertebrate host and apparently infect only insects. we present compelling bioinformatic evidence for a 253-295 codon overlapping gene (designated fifo) conserved throughout these insect-specific flavivi ...201020097399
the ns5 protein of the virulent west nile virus ny99 strain is a potent antagonist of type i interferon-mediated jak-stat signaling.flaviviruses transmitted by arthropods represent a tremendous disease burden for humans, causing millions of infections annually. all vector-borne flaviviruses studied to date suppress host innate responses to infection by inhibiting alpha/beta interferon (ifn-alpha/beta)-mediated jak-stat signal transduction. the viral nonstructural protein ns5 of some flaviviruses functions as the major ifn antagonist, associated with inhibition of ifn-dependent stat1 phosphorylation (py-stat1) or with stat2 d ...201020106931
perspectives for preventive and therapeutic hpv vaccines.human papillomavirus (hpv) has been associated with several human cancers, including cervical cancer, vulvar cancer, vaginal and anal cancer, and a subset of head and neck cancers. thus effective vaccination against hpv provides an opportunity to reduce the morbidity and mortality associated with hpv. the food and drug administration of the united states has approved two preventive vaccines to limit the spread of hpv. however, these are unlikely to impact upon hpv prevalence and cervical cancer ...201020123582
viral pathogenesis in mice is similar for west nile virus derived from mosquito and mammalian cells.west nile virus (wnv) is a mosquito-borne pathogen. during replication, wnv acquires different carbohydrates and lipid membranes, depending on its mosquito or vertebrate hosts. consequently, wnv derived from mosquito and vertebrate cell lines differ in their infectivity for dendritic cells (dcs) and induction of type i interferon (ifn-alpha/beta) in vitro. we evaluated the pathogenesis of wnv derived from mosquito (wnv(c6/36)) and vertebrate (wnv(bhk)) cell lines in mice. the tissue tropism, inf ...201020167345
immunotherapy for cervical cancer: research status and clinical potential.the high-risk types of human papillomavirus (hpv) have been found to be associated with most cervical cancers and play an essential role in the pathogenesis of the disease. despite recent advances in preventive hpv vaccine development, such preventive vaccines are unlikely to reduce the prevalence of hpv infections within the next few years, due to their cost and limited availability in developing countries. furthermore, preventive hpv vaccines may not be capable of treating established hpv infe ...201020199126
both e protein glycans adversely affect dengue virus infectivity but are beneficial for virion release.the e protein of most flaviviruses is modified by asn-linked glycosylation at residue 153/154 and in the case of the four dengue virus (denv) serotypes by a second glycan at residue 67. however, the absence of e protein glycosylation among numerous natural isolates of different flaviviruses suggests that the glycan, per se, is not critically important in the virus life cycle. consistent with this notion, we show that ablation of both glycans from the denv-2 e protein reduces but does not prevent ...201020219924
flavitrack analysis of the structure and function of west nile non-structural proteins.the flavitrack database groups flaviviruses (fv), evolutionarily related organisms with high subtype variability, according to their phenotypes. here, pcpmer tools were used to calculate consensus sequences based on conservation of physicochemical properties (pcp) for 919 sequences of ns2a, a non-structural protein involved in preventing host interferon response to infection. conserved pcp-motifs were detected, primarily in the n-terminal half of ns2a. one model structure, based on a nuclear rec ...201020223736
interplay of rna elements in the dengue virus 5' and 3' ends required for viral rna replication.dengue virus (denv) is a member of the flavivirus genus of positive-sense rna viruses. denv rna replication requires cyclization of the viral genome mediated by two pairs of complementary sequences in the 5' and 3' ends, designated 5' and 3' cyclization sequences (5'-3' cs) and the 5' and 3' upstream of aug region (5'-3' uar). here, we demonstrate that another stretch of six nucleotides in the 5' end is involved in denv replication and possibly genome cyclization. this new sequence is located do ...201020357095
mkrn1 induces degradation of west nile virus capsid protein by functioning as an e3 ligase.west nile virus capsid protein (wnvcp) displays pathogenic toxicity via the apoptotic pathway. however, a cellular mechanism protective against this toxic effect has not been observed so far. here, we identified makorin ring finger protein 1 (mkrn1) as a novel e3 ubiquitin ligase for wnvcp. the cytotoxic effects of wnvcp as well as its expression levels were inhibited in u2os cells that stably expressed mkrn1. immunoprecipitation analyses revealed an interaction between mkrn1 and wnvcp. domain a ...201019846531
present and future arboviral threats.arthropod-borne viruses (arboviruses) are important causes of human disease nearly worldwide. all arboviruses circulate among wild animals, and many cause disease after spillover transmission to humans and agriculturally important domestic animals that are incidental or dead-end hosts. viruses such as dengue (denv) and chikungunya (chikv) that have lost the requirement for enzootic amplification now produce extensive epidemics in tropical urban centers. many arboviruses recently have increased i ...201019857523
viral reorganization of the secretory pathway generates distinct organelles for rna replication.many rna viruses remodel intracellular membranes to generate specialized sites for rna replication. how membranes are remodeled and what properties make them conducive for replication are unknown. here we show how rna viruses can manipulate multiple components of the cellular secretory pathway to generate organelles specialized for replication that are distinct in protein and lipid composition from the host cell. specific viral proteins modulate effector recruitment by arf1 gtpase and its guanin ...201020510927
west nile virus.west nile virus (wnv) is responsible for thousands of cases of morbidity and mortality in birds, horses, and humans. epidemics were localized to europe, africa, the middle east, and parts of asia, and primarily caused a mild febrile illness in humans. in the late 1990s, the virus became more virulent and spread to north america. in humans, the clinical presentation ranges from asymptomatic, seen frequently, to encephalitis/paralysis and death, seen rarely. there is no fda (food and drug administ ...201020513541
experimental studies of the role of the little raven (corvus mellori) in surveillance for west nile virus in australia.to study the potential role of an australian corvid, the little raven (corvus mellori), in the surveillance for exotic west nile virus (wnv) in australia.201020553567
tick-borne encephalitis virus delays interferon induction and hides its double-stranded rna in intracellular membrane vesicles.tick-borne encephalitis virus (tbev) (family flaviviridae, genus flavivirus) accounts for approximately 10,000 annual cases of severe encephalitis in europe and asia. here, we investigated the induction of the antiviral type i interferons (ifns) (alpha/beta ifn [ifn-alpha/beta]) by tbev. using strains neudörfl, hypr, and absettarov, we demonstrate that levels of ifn-beta transcripts and viral rna are strictly correlated. moreover, ifn induction by tbev was dependent on the transcription factor i ...201020554782
meta-analysis of all immune epitope data in the flavivirus genus: inventory of current immune epitope data status in the context of virus immunity and immunopathology.a meta-analysis was performed in order to inventory the immune epitope data related to viruses in the genus flavivirus. nearly 2000 epitopes were captured from over 130 individual flavivirus-related references identified from pubmed and reported as of september 2009. this report includes all epitope structures and associated immune reactivity from the past and current literature, including: the epitope distribution among pathogens and related strains, the epitope distribution among different pat ...201020565291
false-positive transcription-mediated amplification assay detection of west nile virus in blood from a patient with viremia caused by an usutu virus infection.detection of west nile virus (wnv) by nucleic acid amplification technology (naat) is used widely to screen blood and organ donations in areas where wnv is endemic. we report a false-positive result of a wnv transcription-mediated amplification assay (tma) in a patient with viremia that was caused by usutu virus, a mosquito-borne flavivirus.201020592138
characterization of dengue virus resistance to brequinar in cell culture.brequinar is an inhibitor of dihydroorotate dehydrogenase, an enzyme that is required for de novo pyrimidine biosynthesis. here we report that brequinar has activity against a broad spectrum of viruses. the compound not only inhibits flaviviruses (dengue virus, west nile virus, yellow fever virus, and powassan virus) but also suppresses a plus-strand rna alphavirus (western equine encephalitis virus) and a negative-strand rna rhabdovirus (vesicular stomatitis virus). using dengue virus serotype ...201020606073
construction of a dengue virus type 4 reporter replicon and analysis of temperature-sensitive mutations in non-structural proteins 3 and 5.replicon systems have been useful to study mechanisms of translation and replication of flavivirus rnas. in this study, we constructed a dengue virus 4 replicon encoding a renilla luciferase (r(luc)) reporter, and six single-residue substitution mutants were generated: l128f and s158p in the non-structural protein (ns) 3 protease domain gene, and n96i, n390a, k437r and m805i in the ns5 gene. the effects of these substitutions on viral rna translation and/or replication were examined by measuring ...201020631089
arboviral encephalitides: transmission, emergence, and pathogenesis.arthropod-borne viruses (arboviruses) are of paramount concern as a group of pathogens at the forefront of emerging and re-emerging diseases. although some arboviral infections are asymptomatic or present with a mild influenza-like illness, many are important human and veterinary pathogens causing serious illness ranging from rash and arthritis to encephalitis and hemorrhagic fever. here, we discuss arboviruses from diverse families (flaviviruses, alphaviruses, and the bunyaviridae) that are cau ...201020652430
structural and functional analyses of a conserved hydrophobic pocket of flavivirus methyltransferase.the flavivirus methyltransferase (mtase) sequentially methylates the n7 and 2'-o positions of the viral rna cap (gpppa-rna → m(7)gpppa-rna → m(7)gpppam-rna), using s-adenosyl-l-methionine (adomet) as a methyl donor. we report here that sinefungin (sin), an adomet analog, inhibits several flaviviruses through suppression of viral mtase. the crystal structure of west nile virus mtase in complex with sin inhibitor at 2.0-å resolution revealed a flavivirus-conserved hydrophobic pocket located next t ...201020685660
the endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex.the cytoplasmic replication of positive-sense rna viruses is associated with a dramatic rearrangement of host cellular membranes. these virus-induced changes result in the induction of vesicular structures that envelop the virus replication complex (rc). in this study, we have extended our previous observations on the intracellular location of west nile virus strain kunjin virus (wnv(kun)) to show that the virus-induced recruitment of host proteins and membrane appears to occur at a pre-golgi st ...201020686019
rna structures required for production of subgenomic flavivirus rna.flaviviruses are a group of single-stranded, positive-sense rna viruses causing ∼100 million infections per year. we have recently shown that flaviviruses produce a unique, small, noncoding rna (∼0.5 kb) derived from the 3' untranslated region (utr) of the genomic rna (grna), which is required for flavivirus-induced cytopathicity and pathogenicity (g. p. pijlman et al., cell host microbe, 4: 579-591, 2008). this rna (subgenomic flavivirus rna [sfrna]) is a product of incomplete degradation of gr ...201020719943
an rna pseudoknot is required for production of yellow fever virus subgenomic rna by the host nuclease xrn1.cells and mice infected with arthropod-borne flaviviruses produce a small subgenomic rna that is colinear with the distal part of the viral 3'-untranslated region (utr). this small subgenomic flavivirus rna (sfrna) results from the incomplete degradation of the viral genome by the host 5'-3' exonuclease xrn1. production of the sfrna is important for the pathogenicity of the virus. this study not only presents a detailed description of the yellow fever virus (yfv) sfrna but, more importantly, des ...201020739539
identification and characterization of a virus-specific continuous b-cell epitope on the prm/m protein of japanese encephalitis virus: potential application in the detection of antibodies to distinguish japanese encephalitis virus infection from west nile virus and dengue virus infections.differential diagnose of japanese encephalitis virus (jev) infection from other flavivirus especially west nile virus (wnv) and dengue virus (dv) infection was greatly hindered for the serological cross-reactive. virus specific epitopes could benefit for developing jev specific antibodies detection methods. to identify the jev specific epitopes, we fully mapped and characterized the continuous b-cell epitope of the prm/m protein of jev.201020858291
direct interaction between two viral proteins, the nonstructural protein 2c and the capsid protein vp3, is required for enterovirus morphogenesis.in spite of decades-long studies, the mechanism of morphogenesis of plus-stranded rna viruses belonging to the genus enterovirus of picornaviridae, including poliovirus (pv), is not understood. numerous attempts to identify an rna encapsidation signal have failed. genetic studies, however, have implicated a role of the non-structural protein 2c(atpase) in the formation of poliovirus particles. here we report a novel mechanism in which protein-protein interaction is sufficient to explain the spec ...201020865167
dendritic cells transfected with her2 antigen-encoding rna replicons cross-prime cd8 t cells and protect mice against tumor challenge.antigen-specific t cells can be induced by direct priming and cross-priming. to investigate cross-priming as a vaccination approach dendritic cells were transfected with cytopathogenic viral rna-replicons that expressed domains of the tumor-associated her2-antigen and injected into mhc-discordant mice that did not allow direct priming. upon tumor challenge 75% of the vaccinated, but none of the mock-vaccinated mice remained tumor-free. the anti-tumor effect required t cells and correlated with t ...201020887827
evaluation of the influenza a replicon for transient expression of recombinant proteins in mammalian cells.recombinant protein expression in mammalian cells has become a very important technique over the last twenty years. it is mainly used for production of complex proteins for biopharmaceutical applications. transient recombinant protein expression is a possible strategy to produce high quality material for preclinical trials within days. viral replicon based expression systems have been established over the years and are ideal for transient protein expression. in this study we describe the evaluat ...201020949004
structural and functional parameters of the flaviviral protease: a promising antiviral drug target.flaviviruses have a single-strand, positive-polarity rna genome that encodes a single polyprotein. the polyprotein is comprised of seven nonstructural (ns) and three structural proteins. the n- and c-terminal parts of ns3 represent the serine protease and the rna helicase, respectively. the cleavage of the polyprotein by the protease is required to produce the individual viral proteins, which assemble a new viral progeny. conversely, inactivation of the protease blocks viral infection. both the ...201021076642
arboviral diseases and malaria in australia, 2008-09: annual report of the national arbovirus and malaria advisory committee.the national notifiable diseases surveillance system received 8,677 notifications of diseases transmitted by mosquitoes in australia from 1 july 2008 to 30 june 2009. the alphaviruses, barmah forest and ross river, accounted for 6,574 (78%) of these notifications during 2008-09. there were 1,009 notifications of dengue virus infection locally-acquired in north queensland and 484 notified cases resulted from overseas travel. notification rates of dengue virus infection for 2008-09, regardless of ...201021090179
phylogeography of west nile virus: from the cradle of evolution in africa to eurasia, australia, and the americas.west nile virus (wnv) is the most widely distributed of the encephalitic flaviviruses and is a major cause of encephalitis, with isolates obtained from all continents, apart from antarctica. subsequent to its divergence from the other members of the japanese encephalitis virus complex, presumably in africa, wnv has diverged into individual lineages that mostly correspond with geographic distribution. here we elucidate the phylogeography and evolutionary history of isolates from lineage 1 of wnv. ...201021159871
west nile virus differentially modulates the unfolded protein response to facilitate replication and immune evasion.for intracellular survival it is imperative that viruses have the capacity to manipulate various cellular responses, including metabolic and biosynthetic pathways. the unfolded protein response (upr) is induced by various external and internal stimuli, including the accumulation of misfolded proteins in the endoplasmic reticulum (er). our previous studies have indicated that the replication and assembly of the flavivirus west nile virus strain kunjin virus (wnv(kun)) is intimately associated wit ...201021191014
long double-stranded rna induces an antiviral response independent of ifn regulatory factor 3, ifn-beta promoter stimulator 1, and ifn.virus infection elicits a robust innate antiviral response dominated by the production of type 1 ifn. in nonprofessional innate immune cells such as fibroblasts, type 1 ifn is rapidly produced following the recognition of viral dsrna and the subsequent activation of the constitutively expressed transcription factor ifn regulatory factor 3 (irf3). although origin, localization, and length are factors in mediating dsrna recognition and binding by cellular dsrna-binding proteins, the biological sig ...200919864603
arboviral diseases and malaria in australia, 2007/08: annual report of the national arbovirus and malaria advisory committee.the national notifiable diseases surveillance system (nndss) received 8,671 notifications of diseases transmitted by mosquitoes in australia for the season 1 july 2007 to 30 june 2008. this represented a 39% increase from the annual average of 6,259 notifications for the previous 5 years. the alphaviruses, barmah forest and ross river, accounted for 7,760 (89%) of these notifications during the 2007/08 season and represents an increase when compared with the mean of the past 5 seasons. detection ...200919877534
bovine viral diarrhea virus ns4b protein is an integral membrane protein associated with golgi markers and rearranged host membranes.very little is known about bvdv ns4b, a protein of approximately 38 kda. however, a missense mutation in ns4b has been implicated in changing bvdv from a cytopathic to noncytopathic virus, suggesting that ns4b might play a role in bvdv pathogenesis. though this is one possible function, it is also likely that ns4b plays a role in bvdv genome replication. for example, bvdv ns4b interacts with ns3 and ns5a, implying that ns4b is part of a complex, which contains bvdv replicase proteins. other poss ...200919887001
molecular targets for flavivirus drug discovery.flaviviruses are a major cause of infectious disease in humans. dengue virus causes an estimated 50 million cases of febrile illness each year, including an increasing number of cases of hemorrhagic fever. west nile virus, which recently spread from the mediterranean basin to the western hemisphere, now causes thousands of sporadic cases of encephalitis annually. despite the existence of licensed vaccines, yellow fever, japanese encephalitis and tick-borne encephalitis also claim many thousands ...200918796313
analysis of flavivirus ns5 methyltransferase cap binding.the flavivirus 2'-o-nucleoside n-terminal rna methyltransferase (mtase) enzyme is responsible for methylating the viral rna cap structure. to increase our understanding of the mechanism of viral rna cap binding we performed a detailed structural and biochemical characterization of the guanosine cap-binding pocket of the dengue (den) and yellow fever (yf) virus mtase enzymes. we solved an improved 2.1 a resolution crystal structure of den2 mtase, new 1.5 a resolution crystal structures of the yf ...200919101564
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