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rna sensors enable human mast cell anti-viral chemokine production and ifn-mediated protection in response to antibody-enhanced dengue virus infection.dengue hemorrhagic fever and/or dengue shock syndrome represent the most serious pathophysiological manifestations of human dengue virus infection. despite intensive research, the mechanisms and important cellular players that contribute to dengue disease are unclear. mast cells are tissue-resident innate immune cells that play a sentinel cell role in host protection against infectious agents via pathogen-recognition receptors by producing potent mediators that modulate inflammation, cell recrui ...201222479521
viral hemorrhagic fevers: advancing the level of treatment.the management of viral hemorrhagic fevers (vhfs) has mainly focused on strict infection control measures, while standard clinical interventions that are provided to patients with other life-threatening conditions are rarely offered to patients with vhfs. despite its complexity, a proper clinical case management of vhfs is neither futile nor is it lacking in scientific rationale. given that patient outcomes improve when treatment is started as soon as possible, development and implementation of ...201222458265
association of mast cell-derived vegf and proteases in dengue shock syndrome.recent in-vitro studies have suggested that mast cells are involved in dengue virus infection. to clarify the role of mast cells in the development of clinical dengue fever, we compared the plasma levels of several mast cell-derived mediators (vascular endothelial cell growth factor [vegf], soluble vegf receptors [svegfrs], tryptase, and chymase) and -related cytokines (il-4, -9, and -17) between patients with differing severity of dengue fever and healthy controls.201222363824
inhibition of cellular autophagy deranges dengue virion maturation.autophagy is an important component of the innate immune response, directly destroying many intracellular pathogens. however, some pathogens, including several rna viruses, subvert the autophagy pathway, or components of the pathway, to facilitate their replication. in the present study, the effect of inhibiting autophagy on the growth of dengue virus was tested using a novel inhibitor, spautin-1 (specific and potent autophagy inhibitor 1). inhibition of autophagy by spautin-1 generated heat-sen ...201223175363
dengue virus type 2 modulates endothelial barrier function through cd73.dengue hemorrhagic fever is characterized by a unique vascular leakage syndrome. the mechanisms of endothelial barrier dysfunction in dengue hemorrhagic fever are not well understood. we examined the modulation of endothelial barrier function in dengue virus type 2 (denv2) infections using primary human umbilical vein endothelial cells. we demonstrated that the increase in endothelial barrier function within 72 hours after denv2 infection is mediated by type i interferon-dependent cd73 up-regula ...201223149581
weather-driven variation in dengue activity in australia examined using a process-based modeling approach.the impact of weather variation on dengue transmission in cairns, australia, was determined by applying a process-based dengue simulation model (densim) that incorporated local meteorologic, entomologic, and demographic data. analysis showed that inter-annual weather variation is one of the significant determinants of dengue outbreak receptivity. cross-correlation analyses showed that densim simulated epidemics of similar relative magnitude and timing to those historically recorded in reported d ...201223166197
light-addressable measurements of cellular oxygen consumption rates in microwell arrays based on phase-based phosphorescence lifetime detection.a digital light modulation system that utilizes a modified commercial digital micromirror device (dmd) projector, which is equipped with a uv light-emitting diode as a light modulation source, has been developed to spatially direct excited light toward a microwell array device to detect the oxygen consumption rate (ocr) of single cells via phase-based phosphorescence lifetime detection. the microwell array device is composed of a combination of two components: an array of glass microwells contai ...201224348889
epimedium koreanum nakai water extract exhibits antiviral activity against porcine epidermic diarrhea virus in vitro and in vivo.porcine epidemic diarrhea virus (pedv) causes diarrhea of pigs age-independently and death of young piglets, resulting in economic loss of porcine industry. we have screened 333 natural oriental herbal medicines to search for new antiviral candidates against pedv. we found that two herbal extracts, kiom 198 and kiom 124, contain significant anti-ped viral effect. kiom 198 and kiom 124 were identified as epimedium koreanum nakai and lonicera japonica thunberg, respectively. the further plaque and ...201223259003
novel antiviral activity of baicalein against dengue virus.dengue is a serious arboviral disease currently with no effective antiviral therapy or approved vaccine available. therefore, finding the effective compound against dengue virus (denv) replication is very important. among the natural compounds, bioflavonoids derived mainly from plants are of interest because of their biological and medicinal benefits.201223140177
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
the rig-i-like receptor lgp2 controls cd8(+) t cell survival and fitness.the rig-i-like receptors (rlrs) signal innate immune defenses upon rna virus infection, but their roles in adaptive immunity have not been clearly defined. here, we showed that the rlr lgp2 was not essential for induction of innate immune defenses, but rather was required for controlling antigen-specific cd8(+) t cell survival and fitness during peripheral t cell-number expansion in response to virus infection. adoptive transfer and biochemical studies demonstrated that t cell-receptor signaling ...201222841161
chimeric hepatitis b core antigen virus-like particles displaying the envelope domain iii of dengue virus type 2.dengue is a global public health problem for which no drug or vaccine is available. currently, there is increasing interest in developing non-replicating dengue vaccines based on a discrete antigenic domain of the major structural protein of dengue viruses (denvs), known as envelope domain iii (ediii). the use of bio-nanoparticles consisting of recombinant viral structural polypeptides, better known as virus-like particles (vlps), has emerged as a potential platform technology for vaccine develo ...201222794664
probing of exosites leads to novel inhibitor scaffolds of hcv ns3/4a proteinase.hepatitis c is a treatment-resistant disease affecting millions of people worldwide. the hepatitis c virus (hcv) genome is a single-stranded rna molecule. after infection of the host cell, viral rna is translated into a polyprotein that is cleaved by host and viral proteinases into functional, structural and non-structural, viral proteins. cleavage of the polyprotein involves the viral ns3/4a proteinase, a proven drug target. hcv mutates as it replicates and, as a result, multiple emerging quasi ...201222768327
evolutionary responses to a constructed niche: ancient mesoamericans as a model of gene-culture coevolution.culture and genetics rely on two distinct but not isolated transmission systems. cultural processes may change the human selective environment and thereby affect which individuals survive and reproduce. here, we evaluated whether the modes of subsistence in native american populations and the frequencies of the abca1*arg230cys polymorphism were correlated. further, we examined whether the evolutionary consequences of the agriculturally constructed niche in mesoamerica could be considered as a ge ...201222768049
one misdated sequence of rabbit hemorrhagic disease virus prevents accurate estimation of its nucleotide substitution rate.the literature is ripe with phylogenetic estimates of nucleotide substitution rates, especially of measurably evolving species such as rna viruses. however, it is not known how robust these rate estimates are to inaccuracies in the data, particularly in sampling dates that are used for molecular clock calibration. here we report on the rate of evolution of the emerging pathogen rabbit hemorrhagic disease virus (rhdv), which has significantly different rates of evolution for the same outer capsid ...201222646287
west nile virus infection causes endocytosis of a specific subset of tight junction membrane proteins.west nile virus (wnv) is a blood-borne pathogen that causes systemic infections and serious neurological disease in human and animals. the most common route of infection is mosquito bites and therefore, the virus must cross a number of polarized cell layers to gain access to organ tissue and the central nervous system. resistance to trans-cellular movement of macromolecules between epithelial and endothelial cells is mediated by tight junction complexes. while a number of recent studies have doc ...201222655077
filovirus research in gabon and equatorial africa: the experience of a research center in the heart of africa.health research programs targeting the population of gabon and equatorial africa at the international center for medical research in franceville (cirmf), gabon, have evolved during the years since its inception in 1979 in accordance with emerging diseases. since the reemergence of ebola virus in central africa, the cirmf "emerging viral disease unit" developed diagnostic tools and epidemiologic strategies and transfers of such technology to support the response of the national public health syst ...201223170174
detection and typing of viruses using broadly sensitive cocktail-pcr and mass spectrometric cataloging: demonstration with dengue virus.virus detection and taxonomic identification of serotypes, strains, or genotypes provide important information relevant for diagnosis, and for the epidemiological characterization and tracking of new strains in an endemic region. in the specific case of dengue virus, rapid serotype identification can also be useful in the treatment of secondary infections that may cause the more severe dengue hemorrhagic fever and dengue shock syndrome. in this work, dengue virus was used as a model to test a ne ...201222579629
virus identification in unknown tropical febrile illness cases using deep sequencing.dengue virus is an emerging infectious agent that infects an estimated 50-100 million people annually worldwide, yet current diagnostic practices cannot detect an etiologic pathogen in ∼40% of dengue-like illnesses. metagenomic approaches to pathogen detection, such as viral microarrays and deep sequencing, are promising tools to address emerging and non-diagnosable disease challenges. in this study, we used the virochip microarray and deep sequencing to characterize the spectrum of viruses pres ...201222347512
a vaccine formulation consisting of nucleocapsid-like particles from dengue-2 and the fusion protein p64k-domain iii from dengue-1 induces a protective immune response against the homologous serotypes in mice.in previous studies we reported the cloning, expression and purification of the capsid protein from dengue-2 virus. subsequently, we described an in vitro-assembly process for the capsid protein, which resulted in nucleocapsid-like particles (recnlps) that induced functional cell-mediated immunity and protection in mice. moreover, our group reported the evaluation in non-human primates of the fusion protein p64k-domain iii from dengue-1 (pd10). this protein proved to be immunogenic and protectiv ...201222750482
biflavonoids of dacrydium balansae with potent inhibitory activity on dengue 2 ns5 polymerase.in order to find new molecules for antiviral drug design, we screened 102 ethyl acetate extracts from new-caledonian flora for antiviral activity against the dengue 2 virus rna-dependant rna polymerase (dv-ns5 rdrp). the leaf extract of dacrydium balansae, which strongly inhibited the dv-ns5, was submitted to bioguided fractionation. four biflavonoids ( 1- 4), three sterols ( 5- 7), and two stilbene derivatives ( 8- 9) were identified and evaluated for their antiviral potential on the dv-ns5 rdr ...201222411725
[screening and identification of dengue virus type 2-specific antigens].to screen and identify dengue virus type 2 specific antigens and establish an enzyme-linked immunosorbent assay (elisa) for detecting dengue virus type 2 antibody.201223174601
in vitro evaluation of antiprotozoal and antiviral activities of extracts from argentinean mikania species.the aim of this study was to investigate the antiprotozoal and antiviral activities of four argentinean mikania species. the organic and aqueous extracts of mikania micrantha, m. parodii, m. periplocifolia, and m. cordifolia were tested on trypanosoma cruzi epimastigotes, leishmania braziliensis promastigotes, and dengue virus type 2. the organic extract of m. micrantha was the most active against t. cruzi and l. braziliensis exhibiting a growth inhibition of 77.6 ± 4.5% and 84.9 ± 6.1%, respect ...201222919289
dengue hemorrhagic fever in an adult traveler returning to japan.we report the case of a japanese traveler who developed dengue hemorrhagic fever (dhf) with a probable secondary infection with dengue virus type 2 (denv-2). dhf usually occurs in children, and rarely in adult travelers. proper and timely interventions can markedly reduce the mortality rate of dhf patients. the expansion of endemic areas and increased frequency of travel to these areas may suggest increased incidence of dhf in non-endemic areas in the near future. early recognition of reinfectio ...201222790145
serotype specificity of recombinant fusion protein containing domain iii and capsid protein of dengue virus 2.recombinant fusion protein containing domain iii of the dengue envelope protein fused to capsid protein from dengue 2 virus was immunogenic and conferred protection in mice against lethal challenge in previously report. here, the antigenic specificity of this recombinant protein using anti-dengue antibodies from mice and humans and the cross-reactive humoral and cellular response induced in immunized mice were evaluated. the homologous anti-dengue antibodies showed a higher reactivity to the rec ...201222554934
comparative evaluation of permissiveness to dengue virus serotype 2 infection in primary rodent macrophages.infection with dengue virus presents a broad clinical spectrum, which can range from asymptomatic cases to severe cases that are characterised by haemorrhagic syndrome and/or shock. the reason for such variability remains unknown. this work evaluated the in vitro permissiveness of mouse, rat, hamster and guinea pig macrophages to infection by dengue virus 2 (denv2). the results established that macrophages derived from the balb/c mouse strain showed higher permissiveness to denv2 infection than ...201222529871
surface modified microprojection arrays for the selective extraction of the dengue virus ns1 protein as a marker for disease.while advances in assay chemistry and detection continue to improve molecular diagnostics technology, blood samples are still collected using the 150-year-old needle/syringe method. surface modified microprojection arrays have been developed as a novel platform for in vivo, needle-free biomarker capture. these devices are gold coated silicon arrays with >20,000 projections per cm(2), which can be applied to the skin for tunable penetration into the epidermis or dermis. the microprojection array ...201222424552
recombinant nucleocapsid-like particles from dengue-2 induce functional serotype-specific cell-mediated immunity in mice.the interplay of different inflammatory cytokines induced during dengue virus infection plays a role in either protection or increased disease severity. in this sense, vaccine strategies incorporating whole virus are able to elicit both functional and pathological responses. therefore, an ideal tetravalent vaccine candidate against dengue should be focused on serotype-specific sequences. in the present work, a new formulation of nucleocapsid-like particles (nlps) obtained from the recombinant de ...201222398317
flavone enhances dengue virus type-2 (ngc strain) infectivity and replication in vero cells.this study investigates the effects of 2-phenyl-1-benzopyran-4-one (flavone) on denv-2 infectivity in vero cells. virus adsorption and attachment and intracellular virus replication were investigated using a foci forming unit assay (ffua) and quantitative rt-pcr, respectively. addition of flavone (100 μg/ml) significantly increased the number of denv-2 foci by 35.66% ± 1.52 and 49.66% ± 2.51 when added during and after virus adsorption to the vero cells, respectively. the average foci size after ...201222374315
structure of the dengue virus glycoprotein non-structural protein 1 by electron microscopy and single-particle analysis.the flavivirus non-structural protein 1 (ns1) is a glycoprotein that is secreted as a soluble hexameric complex during the course of natural infection. growing evidence indicates that this secreted form of ns1 (sns1) plays a significant role in immune evasion and modulation during infection. attempts to determine the crystal structure of ns1 have been unsuccessful to date and relatively little is known about the macromolecular organization of the sns1 hexamer. here, we have applied single-partic ...201222238236
dengue-2 virus carrying capacity of thai aedes aegypti strains with different susceptibility to deltamethrin.deltamethrin-resistant aedes aegypti currently threatens the effectiveness of dengue hemorrhagic fever control operations in thailand. although a previous study has suggested that insecticide resistance may increase ae. aegypti susceptibility to dengue-2 virus infection, our experimental data showed no significant association between laboratory-induced deltamethrin-resistance in a thai ae. aegypti isolate and its susceptibility to dengue -2 infection.201223077842
chemoproteomic profiling identifies changes in dna-pk as markers of early dengue virus infection.many cellular factors are regulated via mechanisms affecting protein conformation, localization, and function that may be undetected by most commonly used rna- and protein-based profiling methods that monitor steady-state gene expression. mass-spectrometry-based chemoproteomic profiling provides alternatives for interrogating changes in the functional properties of proteins that occur in response to biological stimuli, such as viral infection. taking dengue virus 2 (dv2) infection as a model sys ...201222999307
development of a humanized antibody with high therapeutic potential against dengue virus type 2.dengue virus (denv) is a significant public health threat in tropical and subtropical regions of the world. a therapeutic antibody against the viral envelope (e) protein represents a promising immunotherapy for disease control.201222563515
induction of ifnα or il-12 depends on differentiation of thp-1 cells in dengue infections without and with antibody enhancement.appropriate induction of the early th1 cytokine il-12 is a critical defense directed against viral infection. we have previously shown that different viruses elicited either il-12 or ifnα dependent th1 reactions. using dengue-2 virus, we sought to explore how dengue-2 induced il-12 or ifnα expression by monocytic and its derived dendritic cells.201223216989
synchrony of sylvatic dengue isolations: a multi-host, multi-vector sir model of dengue virus transmission in senegal.isolations of sylvatic dengue-2 virus from mosquitoes, humans and non-human primates in senegal show synchronized multi-annual dynamics over the past 50 years. host demography has been shown to directly affect the period between epidemics in other pathogen systems, therefore, one might expect unsynchronized multi-annual cycles occurring in hosts with dramatically different birth rates and life spans. however, in senegal, we observe a single synchronized eight-year cycle across all vector species ...201223209867
characterization of a model of lethal dengue virus 2 infection in c57bl/6 mice deficient in the alpha/beta interferon receptor.dengue virus (denv) causes dengue fever and dengue haemorrhagic fever/dengue shock syndrome, both considered major public-health problems worldwide. we generated a lethal denv-2 strain (d220) by 10 additional cycles of subcutaneous inoculation of mice with supernatant from mosquito cells infected with the previously characterized strain d2s10, followed by harvesting of serum. d220 induces mortality at ten-fold lower doses than d2s10 in mice lacking only the alpha/beta interferon (ifn-α/β) recept ...201222815273
phylogenetic reconstruction of dengue virus type 2 in colombia.dengue fever is perhaps the most important viral re-emergent disease especially in tropical and sub-tropical countries, affecting about 50 million people around the world yearly. in colombia, dengue virus was first detected in 1971 and still remains as a major public health issue. although four viral serotypes have been recurrently identified, dengue virus type 2 (denv-2) has been involved in the most important outbreaks during the last 20 years, including 2010 when the fatality rate highly incr ...201222405440
characterization of 8-hydroxyquinoline derivatives containing aminobenzothiazole as inhibitors of dengue virus type 2 protease in vitro.four serotypes of dengue virus (denv1-4), mosquito-borne members of flaviviridae family cause frequent epidemics causing considerable morbidity and mortality in humans throughout tropical regions of the world. there is no vaccine or antiviral therapeutics available for human use. in a previous study, we reported that compounds containing the 8-hydroxyquinoline (8-hq) scaffold as inhibitors of west nile virus serine protease. in this study, we analyzed potencies of some compounds with (8-hq)-amin ...201223127365
recovery of live virus after storage at ambient temperature using vivest™.a major impediment to performing virological field studies in developing nations is the lack of ultra-low freezers as well as the expense and difficulty of shipping frozen samples. a commercially available product, vivest™, was developed to preserve nucleic acids at ambient temperature for use in specimen storage and transportation. however, its applications as a viral storage, transport and recovery device have not been evaluated.201223046621
low sensitivity of ns1 protein tests evidenced during a dengue type 2 virus outbreak in santos, brazil, in 2010.in 2010, a large outbreak of dengue occurred in santos, brazil. the detection of the ns1 antigen was used for diagnosis in addition to the detection of igg, igm, and rna. a large number of ns1 false-negative results were obtained. a total of 379 rna-positive samples were selected for thorough evaluation. ns1 was reactive in 37.7% of cases. most of the cases were characterized as a secondary infection by dengue 2 virus. sequencing of ns1 positive and negative isolates did not reveal any mutation ...201223100478
additive protection by antioxidant and apoptosis-inhibiting effects on mosquito cells with dengue 2 virus infection.cytopathic effects (cpes) in mosquito cells are generally trivial compared to those that occur in mammalian cells, which usually end up undergoing apoptosis during dengue virus (denv) infection. however, oxidative stress was detected in both types of infected cells. despite this, the survival of mosquito cells benefits from the upregulation of genes related to antioxidant defense, such as glutathione s transferase (gst). a second defense system, i.e., consisting of antiapoptotic effects, was als ...201222530071
the synergistic effect of combined immunization with a dna vaccine and chimeric yellow fever/dengue virus leads to strong protection against dengue.the dengue envelope glycoprotein (e) is the major component of virion surface and its ectodomain is composed of domains i, ii and iii. this protein is the main target for the development of a dengue vaccine with induction of neutralizing antibodies. in the present work, we tested two different vaccination strategies, with combined immunizations in a prime/booster regimen or simultaneous inoculation with a dna vaccine (pe1d2) and a chimeric yellow fever/dengue 2 virus (yf17d-d2). the pe1d2 dna va ...201323472186
vectorial capacity of aedes aegypti for dengue virus type 2 is reduced with co-infection of metarhizium anisopliae.aedes aegypti, is the major dengue vector and a worldwide public health threat combated basically by chemical insecticides. in this study, the vectorial competence of ae. aegypti co-infected with a mildly virulent metarhizium anisopliae and fed with blood infected with the denv-2 virus, was examined.201323505581
flavonoid from carica papaya inhibits ns2b-ns3 protease and prevents dengue 2 viral assembly.dengue virus belongs to the virus family flaviviridae. dengue hemorrhagic disease caused by dengue virus is a public health problem worldwide. the viral non structural 2b and 3 (ns2b-ns3) protease complex is crucial for virus replication and hence, it is considered to be a good anti-viral target. leaf extracts from carica papaya is generally prescribed for patients with dengue fever, but there are no scientific evidences for its anti-dengue activity; hence we intended to investigate the anti-vir ...201324307765
lipidated dengue-2 envelope protein domain iii independently stimulates long-lasting neutralizing antibodies and reduces the risk of antibody-dependent enhancement.dengue virus is a mosquito-transmitted virus that can cause self-limiting dengue fever, severe life-threatening dengue hemorrhagic fever and dengue shock syndrome. the existence of four serotypes of dengue virus has complicated the development of an effective and safe dengue vaccine. recently, a clinical phase 2b trial of sanofi pasteur's cyd tetravalent dengue vaccine revealed that the vaccine did not confer full protection against dengue-2 virus. new approaches to dengue vaccine development ar ...201324069487
evaluation of protective efficacy using a nonstructural protein ns1 in dna vaccine-loaded microspheres against dengue 2 virus.dengue virus results in dengue fever or severe dengue hemorrhagic fever/dengue shock syndrome in humans. the purpose of this work was to develop an effective antidengue virus delivery system, by designing poly (dl-lactic-co-glycolic) acid/polyethylene glycol (plga/peg) microspheres using a double-emulsion solvent extraction method, for vaccination therapy based on locally and continuously sustained biological activity. nonstructural protein 1 (ns1) in deoxyribonucleic acid (dna) vaccine-loaded p ...201323990724
effects of cocktail of four local malaysian medicinal plants (phyllanthus spp.) against dengue virus 2.the absence of commercialized vaccines and antiviral agents against dengue has made the disease a major health concern around the world. with the current dengue virus transmission rate and incidences, the development of antiviral drugs is of vital need. the aim of this project was to evaluate the possibility of developing a local medicinal plant, phyllanthus as an anti-dengue agent.201323889893
inhibition of dengue virus 2 replication by artificial micrornas targeting the conserved regions.dengue virus (denv), a mosquito-borne flavivirus, causes serious diseases and threatens public health in tropical and subtropical areas worldwide. rna interference (rnai) is a prevailing strategy for antiviral therapy. in this paper, 6 single artificial micrornas (amirnas) targeting the highly conserved regions of the denv-2 genome were identified and inhibited virus replication efficiently. then, effective tandem amirnas targeting 2 different denv-2 genome regions were constructed and expressed ...201323651254
total chemical synthesis of dengue 2 virus capsid protein via native chemical ligation: role of the conserved salt-bridge.the dengue capsid protein c is a highly basic alpha-helical protein of ~100 amino acid residues that forms an emphipathic homodimer to encapsidate the viral genome and to interact with viral membranes. the solution structure of dengue 2 capsid protein c (den2c) has been determined by nmr spectroscopy, revealing a large dimer interface formed almost exclusively by hydrophobic residues. the only acidic residue (glu87) conserved in the capsid proteins of all four serotypes of dengue virus forms a s ...201323673222
viperin is induced following dengue virus type-2 (denv-2) infection and has anti-viral actions requiring the c-terminal end of viperin.the host protein viperin is an interferon stimulated gene (isg) that is up-regulated during a number of viral infections. in this study we have shown that dengue virus type-2 (denv-2) infection significantly induced viperin, co-incident with production of viral rna and via a mechanism requiring retinoic acid-inducible gene i (rig-i). viperin did not inhibit denv-2 entry but denv-2 rna and infectious virus release was inhibited in viperin expressing cells. conversely, denv-2 replicated to higher ...201323638199
a chimeric dengue virus vaccine using japanese encephalitis virus vaccine strain sa14-14-2 as backbone is immunogenic and protective against either parental virus in mice and nonhuman primates.the development of a safe and efficient dengue vaccine represents a global challenge in public health. chimeric dengue viruses (denv) based on an attenuated flavivirus have been well developed as vaccine candidates by using reverse genetics. in this study, based on the full-length infectious cdna clone of the well-known japanese encephalitis virus live vaccine strain sa14-14-2 as a backbone, a novel chimeric dengue virus (named chindenv) was rationally designed and constructed by replacement wit ...201324109223
reduced sphingosine kinase 1 activity in dengue virus type-2 infected cells can be mediated by the 3' untranslated region of dengue virus type-2 rna.sphingosine kinase 1 (sphk1) is a lipid kinase with important roles including regulation of cell survival. we have previously shown reduced sphk1 activity in cells with an established dengue virus type-2 (denv-2) infection. in this study, we examined the effect of alterations in sphk1 activity on denv-2 replication and cell death and determined the mechanisms of the reduction in sphk1 activity. chemical inhibition or overexpression of sphk1 after established denv-2 infection had no effect on inf ...201323939980
prevalence of antibodies to alphaviruses and flaviviruses in free-ranging game animals and nonhuman primates in the greater congo basin.vector-borne and zoonotic pathogens have comprised a significant proportion of the emerging infectious diseases in humans in recent decades. the role of many wildlife species as reservoirs for arthropod-borne viral pathogens is poorly understood. we investigated the exposure history of various african wildlife species from the congo basin to mosquito-borne flaviviruses and alphaviruses by testing archived serum samples. sera from 24 african forest buffalo (syncerus caffer nanus), 34 african elep ...201323778608
chemistry and antiviral activity of arrabidaea pulchra (bignoniaceae).the aim of the present work was to carry out a bioguided isolation of antiviral chemical constituents from an ethanol extract of leaves from arrabidaea pulchra (cham.) sandwith (eeapl) that had shown in vitro activity in a previous screening using dna and rna viruses. the activity of eepal was evaluated against the dna viruses human herpesvirus 1 (hsv-1) and vaccinia virus western reserve (vacv-wr) as well as against the rna viruses murine encephalomyocarditis virus (emcv), and dengue virus 2 (d ...201323959197
complete genome sequencing and evolutionary analysis of indian isolates of dengue virus type 2.dengue is the most important arboviral infection of global public health significance. it is now endemic in most parts of the south east asia including india. though dengue virus type 2 (denv-2) is predominantly associated with major outbreaks in india, complete genome information of indian denv-2 is not available. in this study, the full-length genome of five denv-2 isolates (four from 2001 to 2011 and one from 1960), from different parts of india was determined. the complete genome of the indi ...201323756811
differentially expressed genes of human microvascular endothelial cells in response to anti-dengue virus ns1 antibodies by suppression subtractive hybridization.it has been previously shown that anti-dengue virus (denv) nonstructural protein ns1 antibodies could act as autoantibodies that direct against one or more of the host's own proteins, which has potential implications for dengue hemorrhagic fever pathogenesis. in the present study, we have employed suppression subtractive hybridization (ssh) to identify the differentially expressed genes from human microvascular endothelial cells (hmec-1) in response to anti-dengue virus type 2 ns1 antibodies (an ...201323697814
[an inverted-repeat rna construct for silencing dengue virus type 2 pre-membrane gene suppresses viral replication in bhk-21 cells].to evaluate the anti-viral effects of a plasmid expressing an inverted-repeat rna targeting dengue virus type-2 (denv-2) pre-membrane (prm) gene.201323688980
t helper (th) 1 and th2 cytokine expression profile in dengue and malaria infection using magnetic bead-based bio-plex assay.dengue and malaria infections are two very common vector-borne diseases annually affecting millions of people around the world. both diseases show a variety of clinical presentations, ranging from mild symptoms of dengue fever (df) to severe dengue hemorrhagic fever (dhf) in dengue infection, and low and high parasitemia in malaria infection. t helper (th)1 and th2 cytokine expressions in mild and severe forms of dengue virus type-2 (denv-2) and plasmodium falciparum infection, were compared to ...201323682435
mutation of the dengue virus type 2 envelope protein heparan sulfate binding sites or the domain iii lateral ridge blocks replication in vero cells prior to membrane fusion.using an infectious cdna clone we engineered seven mutations in the putative heparan sulfate- and receptor-binding motifs of the envelope protein of dengue virus serotype 2, strain 16681. four mutant viruses, kk122/123ee, e202k, g304k, and kkk305/307/310eee, were recovered following transfection of c6/36 cells. a fifth mutant, kk291/295ee, was recovered from c6/36 cells with a compensatory e295v mutation. all mutants grew in and mediated fusion of virus-infected c6/36 cells, but three of the mut ...201323571092
structure and dynamics of the monomer of protein e of dengue virus type 2 with unprotonated histidine residues.the surface of the dengue virus is composed of 180 copies of a multifunctional envelope glycoprotein that acts at several stages of viral infection. when the virus is in the endosome, these glycoproteins undergo major conformational rearrangements owing to the protonation of histidine side chains. this protonation allows for the formation of trimers, thereby triggering fusion between the viral and the host membranes. in this study, we examined the behavior of a monomer of this key protein contai ...201323420360
virus-like particles displaying envelope domain iii of dengue virus type 2 induce virus-specific antibody response in mice.currently, dengue represents one of the most significant arboviral disease worldwide, for which a vaccine is not yet available. persistent challenges in live viral dengue vaccines have sparked a keen interest in exploring non-replicating dengue vaccines. we have examined the feasibility of using the methylotrophic yeast pichia pastoris to develop a chimeric vaccine candidate displaying the dengue virus type-2 (denv-2) envelope domain iii (ediii), implicated in host receptor binding and in the in ...201323261049
new pockets in dengue virus 2 surface identified by molecular dynamics simulation.one of the factors limiting the search of new compounds based on the structure of target proteins involved in diseases is the limited amount of target structural information. great advances in the search for lead compounds could be achieved to find new cavities in protein structures that are generated using well established computational chemistry tools. in the case of dengue, the discovery of pockets in the crystallographic structure of the e protein has contributed to the search for lead compo ...201323197323
detection and sequencing of defective viral genomes in c6/36 cells persistently infected with dengue virus 2.dengue virus is the most important arbovirus that affects humans, and it can establish persistent infections, especially in insect-derived cell cultures. defective viral genomes have been implicated in the establishment and maintenance of persistent infections with several flaviviruses; however, there exists almost no information concerning defective dengue virus genomes. here, we report the detection of defective dengue 2 virus genomes in persistently infected mosquito c6/36 cells. the defectiv ...201323129130
diversity and composition of dengue virus type 2 in venezuela.dengue is a mosquito-borne disease caused by four closely related dengue virus (genus flavivirus)serotypes (denv-1–4). the clinical outcomes vary from mild febrile illness to life-threatening haemorrhagic manifestations. denvs are endemic in the tropics and subtropics globally and currently no specific treatment or vaccines are available. in venezuela, the american-asian genotype of denv-2 is the most prevalent and has been associated with severe disease outcomes.we aimed to follow-up the molecu ...201323110744
identification of b cell epitopes of dengue virus 2 ns3 protein by monoclonal antibody.dengue virus is a major international public health concern, and there is a lack of available effective vaccines. virus-specific epitopes could help in developing epitope peptide vaccine. previously, a neutralizing monoclonal antibody (mab) 4f5 against nonstructural protein 3 (ns3) of dengue virus 2 (dv2) was developed in our lab. in this work, the b cell epitope recognized by mab 4f5 was identified using the phage-displayed peptide library. the results of the binding assay and competitive inhib ...201323081772
modulation of enzymatic activity of dengue virus nonstructural protein ns3 nucleoside triphosphatase/helicase by poly(u).the nonstructural protein 3 (ns3) appears to be the most promising target for anti-flavivirus therapy because of its multiple enzymatic activities that are indispensable for virus replication. ns3 of dengue virus type 2 (den2) is composed of two domains, a serine protease in the n-terminal domain (ns3pro) and rna-stimulated nucleoside triphosphatase (ntpase)/rna helicase at the c-terminus (ns3h). ns3 plays an important role in viral replication and the coordinated regulation of all the catalytic ...201324228882
olive baboons: a non-human primate model for testing dengue virus type 2 replication.this study evaluated the use of a non-human primate, the olive baboon (papio anubis), as a model of dengue infection. olive baboons closely resemble humans genetically and physiologically and have been used extensively for assessing novel vaccine formulations.201324139794
dengue virus type 2: protein binding and active replication in human central nervous system cells.an increased number of dengue cases with neurological complications have been reported in recent years. the lack of reliable animal models for dengue has hindered studies on dengue virus (denv) pathogenesis and cellular tropism in vivo. we further investigate the tropism of denv for the human central nervous system (cns), characterizing denv interactions with cell surface proteins in human cns cells by virus overlay protein binding assays (vopba) and coimmunoprecipitations. in vopba, three membr ...201324302878
vector competence of aedes albopictus and aedes aegypti (diptera: culicidae) for den2-43 and new guinea c virus strains of dengue 2 virus.the vector competence of aedes albopictus and aedes aegypti with regard to den2-43 and new guinea c (ngc) virus strains of dengue 2 viruses was assessed and compared. the infection and dissemination rate and distribution of den2-43 antigens in orally infected ae. albopictus was investigated using the reverse transcription polymerase chain reaction and an indirect immunofluorescence assay. to better understand the initial infection, dissemination and transmission of these viral strains in vector ...201323962388
purified and highly aggregated chimeric protein diiic-2 induces a functional immune response in mice against dengue 2 virus.it was previously reported that diiic-2 (a fusion protein composed of domain iii of the envelope protein and the capsid protein from dengue 2 virus), as an aggregate antigen from a partially purified preparation, induced a functional protective immune response against dengue 2 virus in the mouse encephalitis model. in the present work, a purification procedure was developed for diiic-2, and soluble and aggregated fractions of the purified protein were characterized and evaluated in mice. the pur ...201322983185
a novel dengue virus inhibitor, bp13944, discovered by high-throughput screening with dengue virus replicon cells selects for resistance in the viral ns2b/ns3 protease.dengue virus (denv) causes disease globally, resulting in an estimated 25 to 100 million new infections per year. no effective denv vaccine is available, and the current treatment is only supportive. thus, there is an urgent need to develop therapeutic agents to cure this epidemic disease. in the present study, we identified a potential small-molecule inhibitor, bp13944, via high-throughput screening (hts) of 60,000 compounds using a stable cell line harboring an efficient luciferase replicon of ...201324145533
dengue virus infection induces autophagy: an in vivo study.we and others have reported that autophagy is induced by dengue viruses (dvs) in various cell lines, and that it plays a supportive role in dv replication. this study intended to clarify whether dv infection could induce autophagy in vivo. furthermore, the effect of dv induced autophagy on viral replication and dv-related pathogenesis was investigated.201324011333
high-level expression of functionally active dengue-2 non-structural antigen 1 production in escherichia coli.detection of nonstructural protein (ns1) is an important diagnostic marker during acute phase of dengue infection. not only for diagnostic purpose, the protein had important role in vaccine design as well, as a candidate for studying virus assembly and maturation. various researchers employed different expression systems and strategies for recombinant ns1 protein production. attempts to express ns1 protein in prokaryotic and yeast expression system result in formation of insoluble protein which ...201324089673
space constrained homology modelling: the paradigm of the rna-dependent rna polymerase of dengue (type ii) virus.protein structure is more conserved than sequence in nature. in this direction we developed a novel methodology that significantly improves conventional homology modelling when sequence identity is low, by taking into consideration 3d structural features of the template, such as size and shape. herein, our new homology modelling approach was applied to the homology modelling of the rna-dependent rna polymerase (rdrp) of dengue (type ii) virus. the rdrp of dengue was chosen due to the low sequenc ...201323986788
dengue virus activates membrane trail relocalization and ifn-α production by human plasmacytoid dendritic cells in vitro and in vivo.dengue displays a broad spectrum of clinical manifestations that may vary from asymptomatic to severe and even fatal features. plasma leakage/hemorrhages can be caused by a cytokine storm induced by monocytes and dendritic cells during dengue virus (denv) replication. plasmacytoid dendritic cells (pdcs) are innate immune cells and in response to virus exposure secrete ifn-α and express membrane trail (mtrail). we aimed to characterize pdc activation in dengue patients and their function under de ...201323755314
the influence of dengue virus serotype-2 infection on aedes aegypti (diptera: culicidae) motivation and avidity to blood feed.dengue virus (denv) is transmitted by aedes aegypti, a species that lives in close association with human dwellings. the behavior of denv-infected mosquitoes needs further investigation, especially regarding the potential influence of denv on mosquito biting motivation and avidity.201323755202
inhibition of enveloped viruses infectivity by curcumin.curcumin, a natural compound and ingredient in curry, has antiinflammatory, antioxidant, and anticarcinogenic properties. previously, we reported that curcumin abrogated influenza virus infectivity by inhibiting hemagglutination (ha) activity. this study demonstrates a novel mechanism by which curcumin inhibits the infectivity of enveloped viruses. in all analyzed enveloped viruses, including the influenza virus, curcumin inhibited plaque formation. in contrast, the nonenveloped enterovirus 71 r ...201323658730
differential expression of apoptosis related genes in selected strains of aedes aegypti with different susceptibilities to dengue virus.aedes aegypti is the principal vector of dengue viruses worldwide. we identified field collected insects with differential susceptibility to dengue-2 virus (denv-2) and used isofemale selection to establish susceptible and refractory strains based on midgut infection barriers. previous experiments had identified higher expression of apoptosis-related genes in the refractory strain. to identify potential molecular mechanisms associated with denv susceptibility, we evaluated the differential expre ...201323593426
age-dependent effects of oral infection with dengue virus on aedes aegypti (diptera: culicidae) feeding behavior, survival, oviposition success and fecundity.aedes aegypti is the main vector of dengue, a disease that is increasing its geographical range as well as incidence rates. despite its public health importance, the effect of dengue virus (denv) on some mosquito traits remains unknown. here, we investigated the impact of denv-2 infection on the feeding behavior, survival, oviposition success and fecundity of ae. aegypti females.201323555838
circulation of different lineages of dengue virus 2, genotype american/asian in brazil: dynamics and molecular and phylogenetic characterization.the american/asian genotype of dengue virus type 2 (denv-2) was introduced into the americas in the 80's. although there is no data showing when this genotype was first introduced into brazil, it was first detected in brazil in 1990. after which the virus spread throughout the country and major epidemics occurred in 1998, 2007/08 and 2010. in this study we sequenced 12 denv-2 genomes obtained from serum samples of patients with dengue fever residing in são josé do rio preto, são paulo (sjrp/sp), ...201323533624
chloroquine inhibits dengue virus type 2 replication in vero cells but not in c6/36 cells.dengue viruses are the most important arthropod-borne viruses in terms of morbidity and mortality in the world. since there is no dengue vaccine available for human use, we have set out to investigate the use of chloroquine as an antiviral drug against dengue. chloroquine, an amine acidotropic drug known to affect intracellular exocytic pathways by increasing endosomal ph, was used in the in vitro treatment of vero and c6/36 cells infected with dengue virus type 2 (denv-2). real-time rt-pcr and ...201323431254
isolation of midgut escape mutants of two american genotype dengue 2 viruses from aedes aegypti.several studies have shown that american genotype dengue 2 viruses (denv2) have reduced viral fitness in the mosquito vector, aedes aegypti, compared to other denv2 genotypes. diminished replication efficiency or inability to efficiently traverse membrane barriers encompassing organs such as the midgut or salivary glands are considered major factors negatively impacting viral fitness in the mosquito.201323937713
dengue virus photo-inactivated in presence of 1,5-iodonaphthylazide (ina) or amt, a psoralen compound (4'-aminomethyl-trioxsalen) is highly immunogenic in mice.two novel methods of dengue virus inactivation using iodonaphthyl azide (ina) and aminomethyl trioxsalen (amt) were compared with traditional virus inactivation by formaldehyde. the amt inactivated dengue-2 virus retained its binding to a panel of 5 monoclonal antibodies specific for dengue-2 envelope protein, whereas inactivation by formaldehyde and ina led to 30-50% decrease in binding. all three inactivated viruses elicited high level virus neutralizing antibodies in vaccinated mice. however, ...201323835446
genome-wide rnai screen identifies novel host proteins required for alphavirus entry.the enveloped alphaviruses include important and emerging human pathogens such as chikungunya virus and eastern equine encephalitis virus. alphaviruses enter cells by clathrin-mediated endocytosis, and exit by budding from the plasma membrane. while there has been considerable progress in defining the structure and function of the viral proteins, relatively little is known about the host factors involved in alphavirus infection. we used a genome-wide sirna screen to identify host factors that pr ...201324367265
dicer-2 processes diverse viral rna species.rna silencing pathways play critical roles in gene regulation, virus infection, and transposon control. rna interference (rnai) is mediated by small interfering rnas (sirnas), which are liberated from double-stranded (ds)rna precursors by dicer and guide the rna-induced silencing complex (risc) to targets. although principles governing small rna sorting into risc have been uncovered, the spectrum of rna species that can be targeted by dicer proteins, particularly the viral rnas present during an ...201323424633
diversion of stress granules and p-bodies during viral infection.rna granules are structures within cells that impart key regulatory measures on gene expression. two general types of rna granules are conserved from yeast to mammals: stress granules (sgs), which contain many translation initiation factors, and processing bodies (p-bodies, pbs), which are enriched for proteins involved in rna turnover. because of the inverse relationship between appearance of rna granules and persistence of translation, many viruses must subvert rna granule function for replica ...201323290869
ehfpi: a database and analysis resource of essential host factors for pathogenic infection.high-throughput screening and computational technology has greatly changed the face of microbiology in better understanding pathogen-host interactions. genome-wide rna interference (rnai) screens have given rise to a new class of host genes designated as essential host factors (ehfs), whose knockdown effects significantly influence pathogenic infections. therefore, we present the first release of a manually-curated bioinformatics database and analysis resource ehfpi (essential host factors for p ...201425414353
model for vaccine design by prediction of b-epitopes of iedb given perturbations in peptide sequence, in vivo process, experimental techniques, and source or host organisms.perturbation methods add variation terms to a known experimental solution of one problem to approach a solution for a related problem without known exact solution. one problem of this type in immunology is the prediction of the possible action of epitope of one peptide after a perturbation or variation in the structure of a known peptide and/or other boundary conditions (host organism, biological process, and experimental assay). however, to the best of our knowledge, there are no reports of gen ...201424741624
acute undifferentiated febrile illness in rural cambodia: a 3-year prospective observational study.in the past decade, malaria control has been successfully implemented in cambodia, leading to a substantial decrease in reported cases. wide-spread use of malaria rapid diagnostic tests (rdts) has revealed a large burden of malaria-negative fever cases, for which no clinical management guidelines exist at peripheral level health facilities. as a first step towards developing such guidelines, a 3-year cross-sectional prospective observational study was designed to investigate the causes of acute ...201424755844
expanding the proteome of an rna virus by phosphorylation of an intrinsically disordered viral protein.the human proteome contains myriad intrinsically disordered proteins. within intrinsically disordered proteins, polyproline-ii motifs are often located near sites of phosphorylation. we have used an unconventional experimental paradigm to discover that phosphorylation by protein kinase a (pka) occurs in the intrinsically disordered domain of hepatitis c virus non-structural protein 5a (ns5a) on thr-2332 near one of its polyproline-ii motifs. phosphorylation shifts the conformational ensemble of ...201425031324
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
microrna-like viral small rna from dengue virus 2 autoregulates its replication in mosquito cells.micrornas (mirnas) are small regulatory rnas that play significant roles in most cellular processes. in the seemingly endless arms race between hosts and pathogens, viruses also encode mirnas that facilitate successful infection. in search of functional mirnas or viral small rnas (vsrnas) encoded by dengue virus (denv), deep sequencing data of virus-infected aedes aegypti mosquitoes were used. from six vsrnas, with candidate stem-loop structures in the 5' and 3' untranslated regions of the viral ...201424550303
a potential role of myeloid dap12-associating lectin (mdl)-1 in the regulation of inflammation in rheumatoid arthritis patients.the pathogenic roles of myeloid dap12-associating lectin-1(mdl-1) and dap12 in human rheumatoid arthritis (ra) remain unknown. frequencies of mdl-1-expressing monocytes in 22 active ra patients, 16 inactive ra patients, 12 osteoarthritis (oa) patients and 10 healthy controls (hc) were determined by flow-cytometry analysis. the mrna expression levels of mdl-1 and dap12 on pbmcs were evaluated by quantitative pcr, and their protein expression levels in the synovium were examined by immunohistochem ...201424465901
life without double-headed non-muscle myosin ii motor proteins.non-muscle myosin ii motor proteins (myosin iia, myosin iib, and myosin iic) belong to a class of molecular motor proteins that are known to transduce cellular free-energy into biological work more efficiently than man-made combustion engines. nature has given a single myosin ii motor protein for lower eukaryotes and multiple for mammals but none for plants in order to provide impetus for their life. these specialized nanomachines drive cellular activities necessary for embryogenesis, organogene ...201425072053
a "microrna-like" small rna expressed by dengue virus? 201424853506
the relationship between the structure of the tick-borne encephalitis virus strains and their pathogenic properties.tick-borne encephalitis virus (tbev) is transmitted to vertebrates by taiga or forest ticks through bites, inducing disease of variable severity. the reasons underlying these differences in the severity of the disease are unknown. in order to identify genetic factors affecting the pathogenicity of virus strains, we have sequenced and compared the complete genomes of 34 far-eastern subtype (fe) tbev strains isolated from patients with different disease severity (primorye, the russian far east). w ...201424740396
inhibition of hepatitis c virus replication by gs-6620, a potent c-nucleoside monophosphate prodrug.as a class, nucleotide inhibitors (nis) of the hepatitis c virus (hcv) nonstructural protein 5b (ns5b) rna-dependent rna polymerase offer advantages over other direct-acting antivirals, including properties, such as pangenotype activity, a high barrier to resistance, and reduced potential for drug-drug interactions. we studied the in vitro pharmacology of a novel c-nucleoside adenosine analog monophosphate prodrug, gs-6620. it was found to be a potent and selective hcv inhibitor against hcv repl ...201424419349
dengue transmission model by means of viremic adult immuno-competent mouse.dengue virus infection manifests in three distinct forms in humans: dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. infection with the virus is a fatal disease; no vaccine is available and prevention depends on interruption of the chain of transmission. the study of dengue viral transmission by mosquitoes is hindered due to the lack of an affordable animal model. in general, immuno-competent mice are used as a simple and inexpensive animal model, but mice are not susceptible t ...201424685121
parallel solution-phase synthesis and general biological activity of a uridine antibiotic analog library.a small library of ninety four uridine antibiotic analogs was synthesized, under the pilot scale library (psl) program of the nih roadmap initiative, from amine 2 and carboxylic acids 33 and 77 in solution-phase fashion. diverse aldehyde, sulfonyl chloride, and carboxylic acid reactant sets were condensed to 2, leading after acid-mediated hydrolysis, to the targeted compounds 3-32 in good yields and high purity. similarly, treatment of 33 with diverse amines and sulfonamides gave 34-75. the coup ...201424661222
rho'ing in and out of cells: viral interactions with rho gtpase signaling.rho gtpases are key regulators of actin and microtubule dynamics and organization. increasing evidence shows that many viruses have evolved diverse interactions with rho gtpase signaling and manipulate them for their own benefit. in this review, we discuss how rho gtpase signaling interferes with many steps in the viral replication cycle, especially entry, replication, and spread. seen the diversity between viruses, it is not surprising that there is considerable variability in viral interaction ...201424691164
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