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vector-virus interactions and transmission dynamics of west nile virus.west nile virus (wnv; flavivirus; flaviviridae) is the cause of the most widespread arthropod-borne viral disease in the world and the largest outbreak of neuroinvasive disease ever observed. mosquito-borne outbreaks are influenced by intrinsic (e.g., vector and viral genetics, vector and host competence, vector life-history traits) and extrinsic (e.g., temperature, rainfall, human land use) factors that affect virus activity and mosquito biology in complex ways. the concept of vectorial capacit ...201324351794
the changing epidemiology of kunjin virus in australia.west nile virus (wnv) is a mosquito-borne virus responsible for outbreaks of viral encephalitis in humans and horses, with particularly virulent strains causing recent outbreaks of disease in eastern europe, the middle east and north america. a strain of wnv, kunjin (wnvkun), is endemic in northern australia and infection with this virus is generally asymptomatic. however in early 2011, an unprecedented outbreak of encephalitis in horses occurred in south-eastern australia, resulting in mortalit ...201324287851
the effect of vaccination coverage and climate on japanese encephalitis in sarawak, malaysia.japanese encephalitis (je) is the leading cause of viral encephalitis across asia with approximately 70,000 cases a year and 10,000 to 15,000 deaths. because je incidence varies widely over time, partly due to inter-annual climate variability effects on mosquito vector abundance, it becomes more complex to assess the effects of a vaccination programme since more or less climatically favourable years could also contribute to a change in incidence post-vaccination. therefore, the objective of this ...201323951373
three-dimensional architecture of tick-borne encephalitis virus replication sites and trafficking of the replicated rna.flavivirus replication is accompanied by the rearrangement of cellular membranes that may facilitate viral genome replication and protect viral components from host cell responses. the topological organization of viral replication sites and the fate of replicated viral rna are not fully understood. we exploited electron microscopy to map the organization of tick-borne encephalitis virus (tbev) replication compartments in infected cells and in cells transfected with a replicon. under both conditi ...201323552408
ecology of west nile virus in north america.the introduction, dispersal and establishment of west nile virus in north america were reviewed, focusing on factors that may have enhanced receptivity and enabled the invasion process. the overwintering persistence of this tropical virus within temperate latitudes was unexpected, but was key in the transition from invasion to endemic establishment. the cascade of temporal events allowing sporadic amplification to outbreak levels was discussed within a future perspective.201324008376
identification of conserved motifs in the west nile virus envelope essential for particle secretion.enveloped viruses utilize cellular membranes to bud from infected cells. the process of virion assembly and budding is often facilitated by the presence of certain conserved motifs within viral proteins in conjunction with cellular factors. we hence examined the west nile virus (wnv) envelope protein for the presence of any such motifs and their functional characterization.201324007503
non-structural protein-1 is required for west nile virus replication complex formation and viral rna synthesis.flavivirus ns1 is a non-structural glycoprotein that is expressed on the cell surface and secreted into the extracellular space, where it acts as an antagonist of complement pathway activation. despite its transit through the secretory pathway and intracellular localization in the lumen of the endoplasmic reticulum and golgi vesicles, ns1 is as an essential gene for flavivirus replication. how ns1 modulates infection remains uncertain given that the viral rna replication complex localizes to the ...201324245822
increased early rna replication by chimeric west nile virus w956ic leads to ips-1-mediated activation of nf-κb and insufficient virus-mediated counteraction of the resulting canonical type i interferon signaling.although infections with "natural" west nile virus (wnv) and the chimeric w956ic wnv infectious clone virus produce comparable peak virus yields in type i interferon (ifn) response-deficient bhk cells, w956ic infection produces higher levels of "unprotected" viral rna at early times after infection. analysis of infections with these two viruses in ifn-competent cells showed that w956ic activated nf-κb, induced higher levels of ifn-β, and produced lower virus yields than wnv strain eg101. ips-1 w ...201323678179
cytoplasmic viruses: rage against the (cellular rna decay) machine. 201324339774
circulation of japanese encephalitis virus in pigs and mosquito vectors within can tho city, vietnam.japanese encephalitis virus (jev) is a mosquito-borne, zoonotic flavivirus causing encephalitis in humans and reproductive disorder in pigs. jev is present in large parts of asia, where urbanization is high. households within and outside can tho city, south vietnam, were selected to monitor circulation of jev. a nested rt-pcr was established to detect the presence of jev in mosquitoes whereas sera from pigs belonging to households within the province were analyzed for the presence of antibodies ...201323593520
european surveillance for west nile virus in mosquito populations.a wide range of arthropod-borne viruses threaten both human and animal health either through their presence in europe or through risk of introduction. prominent among these is west nile virus (wnv), primarily an avian virus, which has caused multiple outbreaks associated with human and equine mortality. endemic outbreaks of west nile fever have been reported in italy, greece, france, romania, hungary, russia and spain, with further spread expected. most outbreaks in western europe have been due ...201324157510
membrane topology and function of dengue virus ns2a protein.flavivirus nonstructural protein 2a (ns2a) is a component of the viral replication complex that functions in virion assembly and antagonizes the host immune response. although flavivirus ns2a is known to associate with the endoplasmic reticulum (er) membrane, the detailed topology of this protein has not been determined. here we report the first topology model of flavivirus ns2a on the er membrane. using dengue virus (denv) ns2a as a model, we show that (i) the n-terminal 68 amino acids are loca ...201323408612
structural complexity of dengue virus untranslated regions: cis-acting rna motifs and pseudoknot interactions modulating functionality of the viral genome.the dengue virus (denv) genome contains multiple cis-acting elements required for translation and replication. previous studies indicated that a 719-nt subgenomic minigenome (denv-mini) is an efficient template for translation and (-) strand rna synthesis in vitro. we performed a detailed structural analysis of denv-mini rna, combining chemical acylation techniques, pb(2+) ion-induced hydrolysis and site-directed mutagenesis. our results highlight protein-independent 5'-3' terminal interactions ...201323531545
altered protein networks and cellular pathways in severe west nile disease in mice.the recent west nile virus (wnv) outbreaks in developed countries, including europe and the united states, have been associated with significantly higher neuropathology incidence and mortality rate than previously documented. the changing epidemiology, the constant risk of (re-)emergence of more virulent wnv strains, and the lack of effective human antiviral therapy or vaccines makes understanding the pathogenesis of severe disease a priority. thus, to gain insight into the pathophysiological pr ...201323874584
vaccines in development against west nile virus.west nile encephalitis emerged in 1999 in the united states, then rapidly spread through the north american continent causing severe disease in human and horses. since then, outbreaks appeared in europe, and in 2012, the united states experienced a new severe outbreak reporting a total of 5,387 cases of west nile virus (wnv) disease in humans, including 243 deaths. so far, no human vaccine is available to control new wnv outbreaks and to avoid worldwide spreading. in this review, we discuss the ...201324084235
development and characterization of the replicon system of japanese encephalitis live vaccine virus sa14-14-2.viral self-replicating sub-genomic replicons represent a powerful tool for studying viral genome replication, antiviral screening and chimeric vaccine development. many kinds of flavivirus replicons have been developed with broad applications.201323442449
west nile virus in the transfusion setting with a special focus on italian preventive measures adopted in 2008-2012 and their impact on blood safety. 201324120610
natural exposure of horses to mosquito-borne flaviviruses in south-east queensland, australia.in 2011 an unprecedented epidemic of equine encephalitis occurred in south-eastern (se) australia following heavy rainfall and severe flooding in the preceding 2-4 months. less than 6% of the documented cases occurred in queensland, prompting the question of pre-existing immunity in queensland horses. a small-scale serological survey was conducted on horses residing in one of the severely flood-affected areas of se-queensland. using a flavivirus-specific blocking-elisa we found that 63% (39/62) ...201324048209
west nile viral infection of equids.west nile virus (wnv) is a flavivirus transmitted between certain species of birds and mosquito vectors. tangential infections of equids and subsequent equine epizootics have occurred historically. although the attack rate has been estimated to be below 10%, mortality rates can approach 50% in horses that present clinical disease. symptoms are most commonly presenting in the form of encephalitis with ataxia as well as limb weakness, recumbency and muscle fasciculation. the most effective strateg ...201324035480
west nile virus. 201324179475
japanese b encephalitis: an overview of the disease and use of chimerivax-je as a preventative vaccine.the japanese encephalitis virus (jev) is endemic in many countries in southern asia and the western pacific rim, with new spread to previously unrecognized countries. it is an important cause of childhood neurological disease associated with permanent neurological sequelae and death. fortunately, je is a vaccine-preventable disease. the chimerivax™-je (sanofi pasteur, lyon, france) is a live-attenuated chimeric vaccine derived from the live-attenuated yellow fever virus, yf17d, which expresses t ...201325134477
s-adenosyl-homocysteine is a weakly bound inhibitor for a flaviviral methyltransferase.the methyltransferase enzyme (mtase), which catalyzes the transfer of a methyl group from s-adenosyl-methionine (adomet) to viral rna, and generates s-adenosyl-homocysteine (adohcy) as a by-product, is essential for the life cycle of many significant human pathogen flaviviruses. here we investigated inhibition of the flavivirus mtase by several adohcy-derivatives. unexpectedly we found that adohcy itself barely inhibits the flavivirus mtase activities, even at high concentrations. adohcy was als ...201324130807
increased pathogenicity of west nile virus (wnv) by glycosylation of envelope protein and seroprevalence of wnv in wild birds in far eastern russia.in this review, we discuss the possibility that the glycosylation of west nile (wn) virus e-protein may be associated with enhanced pathogenicity and higher replication of wn virus. the results indicate that e-protein glycosylation allows the virus to multiply in a heat-stable manner and therefore, has a critical role in enhanced viremic levels and virulence of wn virus in young-chick infection model. the effect of the glycosylation of the e protein on the pathogenicity of wn virus in young chic ...201324351738
west nile virus genome with glycosylated envelope protein and deletion of alpha helices 1, 2, and 4 in the capsid protein is noninfectious and efficiently secretes subviral particles.flavivirus genomes with deletions in the capsid (c) gene are attractive vaccine candidates, as they secrete highly immunogenic subviral particles (svps) without generating infectious virus. here, we report that cytomegalovirus promoter-driven cdna of west nile virus kunjin (kunv) containing a glycosylation motif in the envelope (e) gene and a combined deletion of alpha helices 1, 2, and 4 in c produces significantly more svps than kunv cdnas with nonglycosylated e and various other deletions in ...201324049184
case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium.encephalitis continues to result in substantial morbidity and mortality worldwide. advances in diagnosis and management have been limited, in part, by a lack of consensus on case definitions, standardized diagnostic approaches, and priorities for research.201323861361
arboviral diseases and malaria in australia, 2010-11: annual report of the national arbovirus and malaria advisory committee.the national notifiable diseases surveillance system (nndss) received notification of 9,291 cases of disease transmitted by mosquitoes during the 2010-11 season (1 july 2010 to 30 june 2011). the alphaviruses barmah forest virus and ross river virus accounted for 7,515 (81%) of these. there were 133 notifications of dengue virus infection acquired in australia and 1,133 cases that were acquired overseas, while for 10 cases, the place of acquisition was unknown. the number of overseas acquired ca ...201323692155
low seroprevalence of murray valley encephalitis and kunjin viruses in an opportunistic serosurvey, victoria 2011.to assess evidence of recent and past exposure to murray valley encephalitis virus (mvev) and west nile clade kunjin virus (kunv) in residents of the murray valley, victoria, during a period of demonstrated activity of both viruses in early 2011.201324090325
molecular characterization and phylogenetic analysis of murray valley encephalitis virus and west nile virus (kunjin subtype) from an arbovirus disease outbreak in horses in victoria, australia, in 2011.virus was detected in the central nervous system (cns) tissue of 11 horses from victoria that died displaying neurological symptoms during an outbreak of disease in australia in 2011. five horses were identified as being infected with murray valley encephalitis virus (mvev) and 6 as being infected with west nile virus subtype kunjin (wnv(kun)). analysis of partial sequence information from the ns5 and e genes indicated that the mvevs within the samples were highly homogenous and all belonged to ...201323345269
simultaneous detection of west nile and japanese encephalitis virus rna by duplex taqman rt-pcr.west nile virus (wnv) and japanese encephalitis virus (jev) are important mosquito-borne viruses of the flaviviridae family, associated with encephalitis, mainly in humans and horses. wnv is also pathogen for many bird species. the incidence of human and animal wnv infections in europe has risen, mostly in recent years, and jev was detected in 2011 in mosquitoes collected in italy and may emerge in europe in the same way as other flaviviruses had emerged recently (usutu and bagaza virus) and sho ...201323892127
clinical and radiological predictors of outcome for murray valley encephalitis.a review of the laboratory-confirmed cases of murray valley encephalitis (mve) from western australia between 2009 and 2011 was conducted to describe the clinical, laboratory, and radiological features of the disease. the nine encephalitis patients presented with altered mental state and seizures, tremor, weakness, or paralysis. all patients developed a raised c-reactive protein, whereas most developed acute liver injury, neutrophilia, and thrombocytosis. all patients with encephalitis developed ...201323296449
comparison of the neuropathology induced by two west nile virus strains.some strains of west nile virus (wnv) are neuroinvasive and may induce fatal encephalitis/meningitis in a variety of animal species including humans. whether, however, there is a strain-specific signature in the brain is as yet unknown. here we investigated the neuropathogenesis induced by two phylogenetically distant wnv strains of lineage 1, wnv(is98) and wnv(kun35 911). while four-week old c57bl/6j mice were susceptible to both strains and succumbed rapidly after intraperitoneal inoculation, ...201324367664
comparison of the live attenuated yellow fever vaccine 17d-204 strain to its virulent parental strain asibi by deep sequencing.the first comparison of a live rna viral vaccine strain to its wild-type parental strain by deep sequencing is presented using as a model the yellow fever virus (yfv) live vaccine strain 17d-204 and its wild-type parental strain, asibi.201324141982
molecular epidemiology and evolution of west nile virus in north america.west nile virus (wnv) was introduced to new york in 1999 and rapidly spread throughout north america and into parts of central and south america. displacement of the original new york (ny99) genotype by the north america/west nile 2002 (na/wn02) genotype occurred in 2002 with subsequent identification of a novel genotype in 2003 in isolates collected from the southwestern unites states region (sw/wn03 genotype). both genotypes co-circulate to date. subsequent wnv surveillance studies have confir ...201324135819
characterization of the mouse neuroinvasiveness of selected european strains of west nile virus.west nile virus (wnv) has caused outbreaks and sporadic infections in central, eastern and mediterranean europe for over 45 years. most strains responsible for the european and mediterranean basin outbreaks are classified as lineage 1. in recent years, wnv strains belonging to lineage 1 and 2 have been causing outbreaks of neuroinvasive disease in humans in countries such as italy, hungary and greece, while mass mortality among birds was not reported. this study characterizes three european stra ...201324058590
regulation of flavivirus rna synthesis and capping.rna viruses, such as flaviviruses, are able to efficiently replicate and cap their rna genomes in vertebrate and invertebrate cells. flaviviruses use several specialized proteins to first make an uncapped negative strand copy of the viral genome that is used as a template for the synthesis of large numbers of capped genomic rnas. despite using relatively simple mechanisms to replicate their rna genomes, there are significant gaps in our understanding of how flaviviruses switch between negative a ...201323929625
exploring the spatio-temporal dynamics of reservoir hosts, vectors, and human hosts of west nile virus: a review of the recent literature.over the last two decades west nile virus (wnv) has been responsible for significant disease outbreaks in humans and animals in many parts of the world. its extremely rapid global diffusion argues for a better understanding of its geographic extent. the purpose of this inquiry was to explore spatio-temporal patterns of wnv using geospatial technologies to study populations of the reservoir hosts, vectors, and human hosts, in addition to the spatio-temporal interactions among these populations. r ...201324284356
a novel platform for virus-like particle-display of flaviviral envelope domain iii: induction of dengue and west nile virus neutralizing antibodies.cd16-rige is a chimeric human membrane glycoprotein consisting of the cd16 ectodomain fused to the transmembrane domain and cytoplasmic tail of the gamma chain of the high affinity receptor of ige (rige). coexpression of cd16-rige and hiv-1 pr55gag polyprotein precursor (pr55gaghiv) in insect cells resulted in the incorporation of cd16-rige glycoprotein into the envelope of extracellular virus-like particles (vlps), a phenomenon known as pseudotyping. taking advantage of this property, we replac ...201323617954
interferon regulatory factor 5-dependent immune responses in the draining lymph node protect against west nile virus infection.upon activation of toll-like and rig-i-like receptor signaling pathways, the transcription factor irf5 translocates to the nucleus and induces antiviral immune programs. the recent discovery of a homozygous mutation in the immunoregulatory gene guanine exchange factor dedicator of cytokinesis 2 (dock2mu/mu) in several irf5-/- mouse colonies has complicated interpretation of immune functions previously ascribed to irf5. to define the antiviral functions of irf5 in vivo, we infected backcrossed ir ...201425031348
host competence and helicase activity differences exhibited by west nile viral variants expressing ns3-249 amino acid polymorphisms.a single helicase amino acid substitution, ns3-t249p, has been shown to increase viremia magnitude/mortality in american crows (amcrs) following west nile virus (wnv) infection. lineage/intra-lineage geographic variants exhibit consistent amino acid polymorphisms at this locus; however, the majority of wnv isolates associated with recent outbreaks reported worldwide have a proline at the ns3-249 residue. in order to evaluate the impact of ns3-249 variants on avian and mammalian virulence, multip ...201424971589
infection with non-lethal west nile virus eg101 strain induces immunity that protects mice against the lethal west nile virus ny99 strain.herein we demonstrate that infection of mice with west nile virus (wnv) eg101 provides protective immunity against lethal challenge with wnv ny99. our data demonstrated that wnv eg101 is largely non-virulent in adult mice when compared to wnv ny99. by day 6 after infection, wnv-specific igm and igg antibodies, and neutralizing antibodies were detected in the serum of all wnv eg101 infected mice. plaque reduction neutralization test data demonstrated that serum from wnv eg101 infected mice neutra ...201424915459
linking pig-tailed macaque major histocompatibility complex class i haplotypes and cytotoxic t lymphocyte escape mutations in simian immunodeficiency virus infection.the influence of major histocompatibility complex class i (mhc-i) alleles on human immunodeficiency virus (hiv) diversity in humans has been well characterized at the population level. mhc-i alleles likely affect viral diversity in the simian immunodeficiency virus (siv)-infected pig-tailed macaque (macaca nemestrina) model, but this is poorly characterized. we studied the evolution of siv in pig-tailed macaques with a range of mhc-i haplotypes. siv(mac251) genomes were amplified from the plasma ...201425275134
a novel t-cell receptor mimic defines dendritic cells that present an immunodominant west nile virus epitope in mice.we used a newly generated t-cell receptor mimic monoclonal antibody (tcrm mab) that recognizes a known nonself immunodominant peptide epitope from west nile virus (wnv) ns4b protein to investigate epitope presentation after virus infection in c57bl/6 mice. previous studies suggested that peptides of different length, either ssvwnattai (10-mer) or ssvwnatta (9-mer) in complex with class i mhc antigen h-2d(b) , were immunodominant after wnv infection. our data establish that both peptides are pres ...201424723377
ultrastructural characterization and three-dimensional architecture of replication sites in dengue virus-infected mosquito cells.during dengue virus infection of host cells, intracellular membranes are rearranged into distinct subcellular structures such as double-membrane vesicles, convoluted membranes, and tubular structures. recent electron tomographic studies have provided a detailed three-dimensional architecture of the double-membrane vesicles, representing the sites of dengue virus replication, but temporal and spatial evidence linking membrane morphogenesis with viral rna synthesis is lacking. integrating techniqu ...201424522909
inhibition of hsp70 reduces porcine reproductive and respiratory syndrome virus replication in vitro.successful viral infection requires the involvement of host cellular factors in their life cycle. heat shock protein 70 (hsp70) can be recruited by numerous viruses to promote the folding, maturation, or assembly of viral proteins. we have previously shown that hsp70 is significantly elevated in porcine reproductive and respiratory syndrome virus (prrsv)-infected lungs, suggesting hsp70 may play a potential role during prrsv infection. in this study, we tried to investigate the role of hsp70 dur ...201424625230
mechanisms underlying the inhibition of interferon signaling by viruses.a hallmark of the antiviral response is the induction of interferons. first discovered in 1957 by issac and lindeman, interferons are noted for their ability to interfere with viral replication. interferons act via autocrine and paracrine pathways to induce an antiviral state in infected cells and in neighboring cells containing interferon receptors. interferons are the frontline defenders against viral infection and their primary function is to locally restrict viral propagation. viruses have e ...201424504013
rna structures that resist degradation by xrn1 produce a pathogenic dengue virus rna.dengue virus is a growing global health threat. dengue and other flaviviruses commandeer the host cell's rna degradation machinery to generate the small flaviviral rna (sfrna), a noncoding rna that induces cytopathicity and pathogenesis. host cell exonuclease xrn1 likely loads on the 5' end of viral genomic rna and degrades processively through ∼10 kb of rna, halting near the 3' end of the viral rna. the surviving rna is the sfrna. we interrogated the architecture of the complete dengue 2 sfrna, ...201424692447
effect of dengue-2 virus infection on protein expression in the salivary glands of aedes aegypti mosquitoes.dengue virus (denv) is the most important mosquito-transmitted flavivirus that is transmitted throughout the tropical and subtropical regions of the world. the primary mosquito vector of denv in urban locations is aedes aegypti. key to understanding the transmission of denv is the relationship between pathogen and vector. accordingly, we report our preliminary characterization of the differentially expressed proteins from ae. aegypti mosquitoes after denv infection. we investigated the virus-vec ...201424445208
monomeric nature of dengue virus ns3 helicase and thermodynamic analysis of the interaction with single-stranded rna.dengue virus nonstructural protein 3 (ns3) is a multifunctional protein formed by a superfamily-2 rna helicase linked to a protease domain. in this work, we report results from in vitro experiments designed to determine the oligomeric state of dengue virus ns3 helicase (ns3h) and to characterize fundamental properties of the interaction with single-stranded (ss)rna. pulsed field gradient-nmr spectroscopy was used to determine the effective hydrodynamic radius of ns3h, which was constant over a w ...201425223789
the west nile virus-like flavivirus koutango is highly virulent in mice due to delayed viral clearance and the induction of a poor neutralizing antibody response.the mosquito-borne west nile virus (wnv) is responsible for outbreaks of viral encephalitis in humans, horses, and birds, with particularly virulent strains causing recent outbreaks of disease in eastern europe, the middle east, north america, and australia. previous studies have phylogenetically separated wnv strains into two main genetic lineages (i and ii) containing virulent strains associated with neurological disease. several wnv-like strains clustering outside these lineages have been ide ...201424942584
modulation of α-enolase post-translational modifications by dengue virus: increased secretion of the basic isoforms in infected hepatic cells.hepatic cells are major sites of dengue virus (denv) replication and liver injury constitutes a characteristic of severe forms of dengue. the role of hepatic cells in dengue pathogenesis is not well established, but since hepatocytes are the major source of plasma proteins, changes in protein secretion by these cells during infection might contribute to disease progression. previously, we showed that denv infection alters the secretion pattern of hepatic hepg2 cells, with α-enolase appearing as ...201425171719
in vitro and in vivo characterization of a west nile virus mad78 infectious clone.the viral determinants governing the varied neuropathogenicity of different west nile virus (wnv) strains are poorly understood. here, we generated an infectious clone (wnv-mad(ic)) of the non-pathogenic strain wnv-mad78 and compared its replication to that of parental wnv-mad78 and a wnv-mad78 infectious clone (wnv-mad(tx-utrs)) containing the 5' and 3' untranslated regions (utrs) of the pathogenic strain wnv-tx. all three viruses replicated at similar rates and caused similar lethality in mice ...201425023336
experimental infection of rhesus macaques and common marmosets with a european strain of west nile virus.west nile virus (wnv) is a mosquito-borne flavivirus that infects humans and other mammals. in some cases wnv causes severe neurological disease. during recent years, outbreaks of wnv are increasing in worldwide distribution and novel genetic variants of the virus have been detected. although a substantial amount of data exists on wnv infections in rodent models, little is known about early events during wnv infection in primates, including humans. to gain a deeper understanding of this process, ...201424743302
the nairovirus nairobi sheep disease virus/ganjam virus induces the translocation of protein disulphide isomerase-like oxidoreductases from the endoplasmic reticulum to the cell surface and the extracellular space.nairobi sheep disease virus (nsdv) of the genus nairovirus causes a haemorrhagic gastroenteritis in sheep and goats with mortality up to 90%; the virus is found in east and central africa, and in india, where the virus is called ganjam virus. nsdv is closely related to the human pathogen crimean-congo haemorrhagic fever virus, which also causes a haemorrhagic disease. as with other nairoviruses, replication of nsdv takes place in the cytoplasm and the new virus particles bud into the golgi appar ...201424714576
sequential conformational rearrangements in flavivirus membrane fusion.the west nile virus (wnv) envelope protein, e, promotes membrane fusion during viral cell entry by undergoing a low-ph triggered conformational reorganization. we have examined the mechanism of wnv fusion and sought evidence for potential intermediates during the conformational transition by following hemifusion of wnv virus-like particles (vlps) in a single particle format. we have introduced specific mutations into e, to relate their influence on fusion kinetics to structural features of the p ...201425479384
applications of a sugar-based surveillance system to track arboviruses in wild mosquito populations.effective arbovirus surveillance is essential to ensure the implementation of control strategies, such as mosquito suppression, vaccination, or dissemination of public warnings. traditional strategies employed for arbovirus surveillance, such as detection of virus or virus-specific antibodies in sentinel animals, or detection of virus in hematophagous arthropods, have limitations as an early-warning system. a system was recently developed that involves collecting mosquitoes in co2-baited traps, ...201424359415
flavivirus detection and differentiation by a microsphere array assay.flaviviruses of the japanese encephalitis virus (jev) serocomplex include major human and animal pathogens that have a propensity to spread and emerge in new geographic areas. different genotypes or genetic lineages have been defined for many of these viruses, and they are distributed worldwide. tools enabling rapid detection of new or emerging flaviviruses and differentiation of important subgroups have widespread application for arbovirus diagnosis and surveillance, and are crucial for detecti ...201424690622
evaluation of a mouse model for the west nile virus group for the purpose of determining viral pathotypes.west nile virus (wnv; family flaviviridae; genus flavivirus) group members are an important cause of viral meningoencephalitis in some areas of the world. they exhibit marked variation in pathogenicity, with some viral lineages (such as those from north america) causing high prevalence of severe neurological disease, whilst others (such as australian kunjin virus) rarely cause disease. the aim of this study was to characterize wnv disease in a mouse model and to elucidate the pathogenetic featur ...201424694397
use of envelope domain iii protein for detection and differentiation of flaviviruses in the free state province, south africa.the presence of the mosquito-borne flavivirus species west nile virus (wnv) and wesselsbron virus (wessv) in southern africa is well established; however, their true prevalence remains unknown. to date, the presence of tick-borne flaviviruses has not been confirmed in this region. serological assays using reagents that can be handled in a biosafety level 2 or lower facility were developed and evaluated for the detection and differentiation of tick- and mosquito-borne flaviviruses in the free sta ...201424689894
aedes albopictus (diptera: culicidae) as a potential vector of endemic and exotic arboviruses in australia.in 2005, established populations of aedes albopictus (skuse) were discovered in the torres strait, the region that separates papua new guinea from northern australia. this increased the potential for this species to be introduced to mainland australia. because it is an arbovirus vector elsewhere, we undertook laboratory-based infection and transmission experiments to determine the potential for ae. albopictus from the torres strait to become infected with and transmit the four major australian e ...201424897860
vector competence of culex neavei and culex quinquefasciatus (diptera: culicidae) from senegal for lineages 1, 2, koutango and a putative new lineage of west nile virus.west nile virus (wn virus) is one of the most widespread arbovirus and exhibits a great genetic diversity with 8 lineages, at least 4 (1, 2, koutango, and putative new) are present in africa. in west africa, culex neavei and culex quinquefasciatus are considered as potential vectors for wn virus transmission in sylvatic or urban context. we analyzed the vector competence of these culex species from senegal for african lineages and envelope proteins sequences of viral strains used. we showed that ...201424567319
a review of the epidemiological and clinical aspects of west nile virus.the resurgence of west nile virus (wnv) in north america and europe in recent years has raised the concerns of local authorities and highlighted that mosquito-borne disease is not restricted to tropical regions of the world. wnv is maintained in enzootic cycles involving, primarily, culex spp. mosquitoes and avian hosts, with epizootic spread to mammals, including horses and humans. human infection results in symptomatic illness in approximately one-fifth of cases and neuroinvasive disease in le ...201424748813
quantitative proteomic analysis of host-virus interactions reveals a role for golgi brefeldin a resistance factor 1 (gbf1) in dengue infection.dengue virus is considered to be the most important mosquito-borne virus worldwide and poses formidable economic and health care burdens on many tropical and subtropical countries. dengue infection induces drastic rearrangement of host endoplasmic reticulum membranes into complex membranous structures housing replication complexes; the contribution(s) of host proteins and pathways to this process is poorly understood but is likely to be mediated by protein-protein interactions. we have developed ...201424855065
the role of viral persistence in flavivirus biology.in nature, vector-borne flaviviruses are persistently cycled between either the tick or mosquito vector and small mammals such as rodents, skunks, and swine. these viruses account for considerable human morbidity and mortality worldwide. increasing and substantial evidence of viral persistence in humans, which includes the isolation of rna by rt-pcr and infectious virus by culture, continues to be reported. viral persistence can also be established in vitro in various human, animal, arachnid, an ...201424737600
safety and immunogenicity of a delta inulin-adjuvanted inactivated japanese encephalitis virus vaccine in pregnant mares and foals.in 2011, following severe flooding in eastern australia, an unprecedented epidemic of equine encephalitis occurred in south-eastern australia, caused by murray valley encephalitis virus (mvev) and a new variant strain of kunjin virus, a subtype of west nile virus (wnvkun). this prompted us to assess whether a delta inulin-adjuvanted, inactivated cell culture-derived japanese encephalitis virus (jev) vaccine (je-advax™) could be used in horses, including pregnant mares and foals, to not only indu ...201425516480
two distinct sets of ns2a molecules are responsible for dengue virus rna synthesis and virion assembly.flavivirus nonstructural protein 2a (ns2a) plays important roles in both viral rna synthesis and virion assembly. the molecular details of how the ns2a protein modulates the two distinct events have not been defined. to address this question, we have performed a systematic mutagenesis of ns2a using dengue virus (denv) serotype 2 (denv-2) as a model. we identified two sets of ns2a mutations with distinct defects during a viral infection cycle. one set of ns2a mutations (d125a and g200a) selective ...201425392211
molecular and immunological characterization of a dna-launched yellow fever virus 17d infectious clone.yellow fever virus (yfv)-17d is an empirically developed, highly effective live-attenuated vaccine that has been administered to human beings for almost a century. yfv-17d has stood as a paradigm for a successful viral vaccine, and has been exploited as a potential virus vector for the development of recombinant vaccines against other diseases. in this study, a dna-launched yfv-17d construct (pbelobac-flyf) was explored as a new modality to the standard vaccine to combine the commendable feature ...201425516543
characterization of the mode of action of a potent dengue virus capsid inhibitor.dengue viruses (dv) represent a significant global health burden, with up to 400 million infections every year and around 500,000 infected individuals developing life-threatening disease. in spite of attempts to develop vaccine candidates and antiviral drugs, there is a lack of approved therapeutics for the treatment of dv infection. we have previously reported the identification of st-148, a small-molecule inhibitor exhibiting broad and potent antiviral activity against dv in vitro and in vivo ...201425056895
substitution of ns5 n-terminal domain of dengue virus type 2 rna with type 4 domain caused impaired replication and emergence of adaptive mutants with enhanced fitness.flavivirus ns3 and ns5 are required in viral replication and 5'-capping. ns3 has ns2b-dependent protease, rna helicase, and 5'-rna triphosphatase activities. ns5 has 5'-rna methyltransferase (mt)/guanylyltransferase (gt) activities within the n-terminal 270 amino acids and the rna-dependent rna polymerase (pol) activity within amino acids 271-900. a chimeric ns5 containing the d4mt/d4gt and the d2pol domains in the context of wild-type (wt) d2 rna was constructed. rnas synthesized in vitro were ...201424904061
epidemiology of west nile disease in europe and in the mediterranean basin from 2009 to 2013.west nile virus (wnv) transmission has been confirmed in the last four years in europe and in the mediterranean basin. an increasing concern towards west nile disease (wnd) has been observed due to the high number of human and animal cases reported in these areas confirming the importance of this zoonosis. a new epidemiological scenario is currently emerging: although new introductions of the virus from abroad are always possible, confirming the epidemiological role played by migratory birds, th ...201425302311
abrogation of tlr3 inhibition by discrete amino acid changes in the c-terminal half of the west nile virus ns1 protein.west nile virus (wnv) is a mosquito-transmitted pathogen, which causes significant disease in humans. the innate immune system is a first-line defense against invading microorganism and many flaviviruses, including wnv, have evolved multifunctional proteins, which actively suppress its activation and antiviral actions. the wnv non-structural protein 1 (ns1) inhibits signal transduction originating from toll-like receptor 3 (tlr3) and also critically contributes to virus genome replication. in th ...201424889229
g3bp1, g3bp2 and caprin1 are required for translation of interferon stimulated mrnas and are targeted by a dengue virus non-coding rna.viral rna-host protein interactions are critical for replication of flaviviruses, a genus of positive-strand rna viruses comprising major vector-borne human pathogens including dengue viruses (denv). we examined three conserved host rna-binding proteins (rbps) g3bp1, g3bp2 and caprin1 in dengue virus (denv-2) infection and found them to be novel regulators of the interferon (ifn) response against denv-2. the three rbps were required for the accumulation of the protein products of several interfe ...201424992036
expression of mosquito microrna aae-mir-2940-5p is downregulated in response to west nile virus infection to restrict viral replication.west nile virus (wnv) is an enveloped virus with a single-stranded positive-sense rna genome from the flaviviridae family. wnv is spread by mosquitoes and able to infect humans, causing encephalitis and meningitis that can be fatal; it therefore presents a significant risk for human health. in insects, innate response to rna virus infection mostly relies on rna interference and jak/sat pathways; however, some evidence indicates that it can also involve micrornas (mirnas). mirnas are small noncod ...201424829359
rna virus reverse genetics and vaccine design.rna viruses are capable of rapid spread and severe or potentially lethal disease in both animals and humans. the development of reverse genetics systems for manipulation and study of rna virus genomes has provided platforms for designing and optimizing viral mutants for vaccine development. here, we review the impact of rna virus reverse genetics systems on past and current efforts to design effective and safe viral therapeutics and vaccines.201424967693
the bioactive lipid 4-hydroxyphenyl retinamide inhibits flavivirus replication.dengue virus (denv), a member of the flaviviridae family, is a mosquito-borne pathogen and the cause of dengue fever. the increasing prevalence of denv worldwide heightens the need for an effective vaccine and specific antivirals. due to the dependence of denv upon the lipid biosynthetic machinery of the host cell, lipid signaling and metabolism present unique opportunities for inhibiting viral replication. we screened a library of bioactive lipids and modulators of lipid metabolism and identifi ...201425313218
seroprevalence screening for the west nile virus in malaysia's orang asli population.west nile virus (wnv) infection is an emerging zoonotic disease caused by an rna virus of the genus flavivirus. wnv is preserved in the environment through cyclic transmission, with mosquitoes, particularly culex species, serving as a vector, birds as an amplifying host and humans and other mammals as dead-end hosts. to date, no studies have been carried out to determine the prevalence of the wnv antibody in malaysia. the aim of this study was to screen for the seroprevalence of the wnv in malay ...201425515627
oxidative stress influences positive strand rna virus genome synthesis and capping.flaviviruses are 5' capped positive-stranded rna viruses that replicate their genomes within endoplasmic reticulum-derived vesicles. flaviviruses are well known to induce oxidative stress late in infection but it is unknown if oxidative stress plays a positive role in the viral rna replication cycle. we therefore examined how oxidation affects flavivirus rna replication. we found that antioxidant treatment reduced virus production, reduced the viral positive-to-negative strand rna ratio, and res ...201425514423
emergence of west nile virus lineage 2 in europe: a review on the introduction and spread of a mosquito-borne disease.west nile virus (wnv) is transmitted by mosquitoes and causes fever and encephalitis in humans, equines, and occasionally wild birds. the virus was first isolated in sub-saharan africa where it is endemic. wnv lineage 1 has been responsible for repeated disease outbreaks in the countries of the mediterranean basin over the past 50 years. this lineage was also introduced into north america in 1999 causing widespread human, equine, and avian mortality. wnv lineage 2, the first wnv lineage to be is ...201425538937
whole genome phylogenetic investigation of a west nile virus strain isolated from a tick sampled from livestock in north eastern kenya.west nile virus (wnv) has a wide geographical distribution and has been associated to cause neurological disease in humans and horses. mosquitoes are the traditional vectors for wnv; however, the virus has also been isolated from tick species in north africa and europe which could be a means of introduction and spread of the virus over long distances through migratory birds. although wnv has been isolated in mosquitoes in kenya, paucity of genetic and pathogenicity data exists. we previously rep ...201425430727
evidence of west nile virus infection in nepal.acute febrile illness is common among those seeking medical care and is frequently treated empirically with the underlying illness remaining undiagnosed in resource-poor countries. a febrile illness study was conducted 2009-2010 to identify known and unknown pathogens circulating in nepal.201425427544
ebola virus vaccines: an overview of current approaches.ebola hemorrhagic fever is one of the most fatal viral diseases worldwide affecting humans and nonhuman primates. although infections only occur frequently in central africa, the virus has the potential to spread globally and is classified as a category a pathogen that could be misused as a bioterrorism agent. as of today there is no vaccine or treatment licensed to counteract ebola virus infections. dna, subunit and several viral vector approaches, replicating and non-replicating, have been tes ...201424575870
development, characterization and application of monoclonal antibodies against brazilian dengue virus isolates.dengue is the most prevalent human arboviral disease. the morbidity related to dengue infection supports the need for an early, quick and effective diagnostic test. brazil is a hotspot for dengue, but no serological diagnostic test has been produced using brazilian dengue virus isolates. this study aims to improve the development of immunodiagnostic methods for dengue virus (denv) detection through the production and characterization of 22 monoclonal antibodies (mabs) against brazilian isolates ...201425412181
estimating the burden of japanese encephalitis virus and other encephalitides in countries of the mekong region.diverse aetiologies of viral and bacterial encephalitis are widely recognized as significant yet neglected public health issues in the mekong region. a robust analysis of the corresponding health burden is lacking. we retrieved 75 articles on encephalitis in the region published in english or in french from 1965 through 2011. review of available data demonstrated that they are sparse and often derived from hospital-based studies with significant recruitment bias. almost half (35 of 75) of articl ...201424498443
dicer-2-dependent activation of culex vago occurs via the traf-rel2 signaling pathway.despite their importance as vectors of human and livestock diseases, relatively little is known about innate antiviral immune pathways in mosquitoes and other insects. previous work has shown that culex vago (cxvago), which is induced and secreted from west nile virus (wnv)-infected mosquito cells, acts as a functional homolog of interferon, by activating jak-stat pathway and limiting virus replication in neighbouring cells. here we describe the dicer-2-dependent pathway leading to wnv-induced c ...201424762775
development of nucleic acid vaccines: use of self-amplifying rna in lipid nanoparticles.self-amplifying rna or rna replicon is a form of nucleic acid-based vaccine derived from either positive-strand or negative-strand rna viruses. the gene sequences encoding structural proteins in these rna viruses are replaced by mrna encoding antigens of interest as well as by rna polymerase for replication and transcription. this kind of vaccine has been successfully assayed with many different antigens as vaccines candidates, and has been shown to be potent in several animal species, including ...201424748793
role of enhanced vector transmission of a new west nile virus strain in an outbreak of equine disease in australia in 2011.in 2011, a variant of west nile virus kunjin strain (wnvkun) caused an unprecedented epidemic of neurological disease in horses in southeast australia, resulting in almost 1,000 cases and a 9% fatality rate. we investigated whether increased fitness of the virus in the primary vector, culex annulirostris, and another potential vector, culex australicus, contributed to the widespread nature of the outbreak.201425499981
evidence of experimental vertical transmission of emerging novel ecsa genotype of chikungunya virus in aedes aegypti.chikungunya virus (chikv) has emerged as one of the most important arboviruses of public health significance in the past decade. the virus is mainly maintained through human-mosquito-human cycle. other routes of transmission and the mechanism of maintenance of the virus in nature are not clearly known. vertical transmission may be a mechanism of sustaining the virus during inter-epidemic periods. laboratory experiments were conducted to determine whether aedes aegypti, a principal vector, is cap ...201425080107
the west nile virus assembly process evades the conserved antiviral mechanism of the interferon-induced mxa protein.flaviviruses have evolved means to evade host innate immune responses. recent evidence suggests this is due to prevention of interferon production and signaling in flavivirus-infected cells. here we show that the interferon-induced mxa protein can sequester the west nile virus strain kunjin virus (wnvkun) capsid protein in cytoplasmic tubular structures in an expression-replication system. this sequestering resulted in reduced titers of secreted wnvkun particles. we show by electron microscopy, ...201424314641
development and field evaluation of the sentinel mosquito arbovirus capture kit (smack).although sentinel animals are used successfully throughout the world to monitor arbovirus activity, ethical considerations and cross-reactions in serological assays highlight the importance of developing viable alternatives. here we outline the development of a passive sentinel mosquito arbovirus capture kit (smack) that allows for the detection of arboviruses on honey-baited nucleic acid preservation cards (flinders technology associates; fta®) and has a similar trap efficacy as standard light ...201526444264
sero-prevalence and cross-reactivity of chikungunya virus specific anti-e2ep3 antibodies in arbovirus-infected patients.chikungunya virus (chikv) and clinically-related arboviruses cause large epidemics with serious economic and social impact. as clinical symptoms of chikv infections are similar to several flavivirus infections, good detection methods to identify chikv infection are desired for improved treatment and clinical management. the strength of anti-e2ep3 antibody responses was explored in a longitudinal study on 38 chikv-infected patients. we compared their anti-e2ep3 responses with those of patients in ...201525568956
japanese encephalitis virus replicon-based vaccine expressing enterovirus-71 epitope confers dual protection from lethal challenges.to construct safer recombinant flavivirus vaccine, we exploited japanese encephalitis virus (jev) replicon-based platform to generate single-round infectious particles (srips) that expressed heterologous neutralizing epitope sp70 derived from enterovirus-71 (ev71). such pseudo-infectious virus particles, named srip-sp70, although are not genuine viable viruses, closely mimic live virus infection to elicit immune responses within one round of viral life cycle.201526362772
standing your ground to exoribonucleases: function of flavivirus long non-coding rnas.members of the flaviviridae (e.g., dengue virus, west nile virus, and hepatitis c virus) contain a positive-sense rna genome that encodes a large polyprotein. it is now also clear most if not all of these viruses also produce an abundant subgenomic long non-coding rna. these non-coding rnas, which are called subgenomic flavivirus rnas (sfrnas) or xrn1-resistant rnas (xrrnas), are stable decay intermediates generated from the viral genomic rna through the stalling of the cellular exoribonuclease ...201526368052
japanese encephalitis virus nonstructural protein ns5 interacts with mitochondrial trifunctional protein and impairs fatty acid β-oxidation.infection with japanese encephalitis virus (jev) can induce the expression of pro-inflammatory cytokines and cause acute encephalitis in humans. β-oxidation breaks down fatty acids for atp production in mitochondria, and impaired β-oxidation can induce pro-inflammatory cytokine expression. to address the role of fatty-acid β-oxidation in jev infection, we measured the oxygen consumption rate of mock- and jev-infected cells cultured with or without long chain fatty acid (lcfa) palmitate. cells wi ...201525816318
flavivirus sfrna suppresses antiviral rna interference in cultured cells and mosquitoes and directly interacts with the rnai machinery.productive arbovirus infections require mechanisms to suppress or circumvent the cellular rna interference (rnai) pathway, a major antiviral response in mosquitoes. in this study, we demonstrate that two flaviviruses, dengue virus and kunjin virus, significantly repress sirna-mediated rnai in infected human cells as well as during infection of the mosquito vector culex quinquefasciatus. arthropod-borne flaviviruses generate a small structured non-coding rna from the viral 3' utr referred to as s ...201526331679
the involvement of microtubules and actin during the infection of japanese encephalitis virus in neuroblastoma cell line, imr32.the role of the cytoskeleton, actin, and microtubules were examined during the process of japanese encephalitis (jev) infection in a human neuroblastoma cell line, imr32. cytochalasin d and nocodazole were used to depolymerise the cellular actin and microtubules, respectively, in order to study the effect of jev infection in the cell. this study shows that depolymerisation of the actin cytoskeleton at early process of infection inhibits jev infection in the cell; however infection was not inhibi ...201525705678
double-stranded rna is detected by immunofluorescence analysis in rna and dna virus infections, including those by negative-stranded rna viruses.early biochemical studies of viral replication suggested that most viruses produce double-stranded rna (dsrna), which is essential for the induction of the host immune response. however, it was reported in 2006 that dsrna could be detected by immunofluorescence antibody staining in double-stranded dna and positive-strand rna virus infections but not in negative-strand rna virus infections. other reports in the literature seemed to support these observations. this suggested that negative-strand r ...201526136565
a basic cluster in the n terminus of yellow fever virus ns2a contributes to infectious particle production.the flavivirus ns2a protein is involved in the assembly of infectious particles. to further understand its role in this process, a charged-to-alanine scanning analysis was performed on ns2a encoded by an infectious cdna clone of yellow fever virus (yfv). fifteen mutants containing single, double, or triple charged-to-alanine changes were tested. five of them did not produce infectious particles, whereas efficient rna replication was detectable for two of the five ns2a mutants (r22a-k23a-r24a and ...201525694595
ecuador paraiso escondido virus, a new flavivirus isolated from new world sand flies in ecuador, is the first representative of a novel clade in the genus flavivirus.a new flavivirus, ecuador paraiso escondido virus (epev), named after the village where it was discovered, was isolated from sand flies (psathyromyia abonnenci, formerly lutzomyia abonnenci) that are unique to the new world. this represents the first sand fly-borne flavivirus identified in the new world. epev exhibited a typical flavivirus genome organization. nevertheless, the maximum pairwise amino acid sequence identity with currently recognized flaviviruses was 52.8%. phylogenetic analysis o ...201526355096
new insights into flavivirus evolution, taxonomy and biogeographic history, extended by analysis of canonical and alternative coding sequences.to generate the most diverse phylogenetic dataset for the flaviviruses to date, we determined the genomic sequences and phylogenetic relationships of 14 flaviviruses, of which 10 are primarily associated with culex spp. mosquitoes. we analyze these data, in conjunction with a comprehensive collection of flavivirus genomes, to characterize flavivirus evolutionary and biogeographic history in unprecedented detail and breadth. based on the presumed introduction of yellow fever virus into the americ ...201525719412
flavivirus rna synthesis in vitro.establishment of in vitro systems to study mechanisms of rna synthesis for positive strand rna viruses have been very useful in the past and have shed light on the composition of protein and rna components, optimum conditions, the nature of the products formed, cis-acting rna elements and trans-acting protein factors required for efficient synthesis. in this review, we summarize our current understanding regarding the requirements for flavivirus rna synthesis in vitro. we describe details of rea ...201526272247
alpha-synuclein expression restricts rna viral infections in the brain.we have discovered that native, neuronal expression of alpha-synuclein (asyn) inhibits viral infection, injury, and disease in the central nervous system (cns). enveloped rna viruses, such as west nile virus (wnv), invade the cns and cause encephalitis, yet little is known about the innate neuron-specific inhibitors of viral infections in the cns. following wnv infection of primary neurons, we found that asyn protein expression is increased. the infectious titer of wnv and venezuelan equine ence ...201526719256
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