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an antiviral role for antimicrobial peptides during the arthropod response to alphavirus replication.alphaviruses establish a persistent infection in arthropod vectors which is essential for the effective transmission of the virus to vertebrate hosts. the development of persistence in insects is not well understood, although it is thought to involve the innate immune response. using a transgenic fly system expressing a self-replicating viral rna genome analog, we have previously demonstrated antiviral roles of the drosophila imd (immune deficiency) and jak-stat innate immunity pathways in respo ...201323365449
venezuelan equine encephalitis virus nsp2 protein regulates packaging of the viral genome into infectious virions.alphaviruses are one of the most geographically widespread and yet often neglected group of human and animal pathogens. they are capable of replicating in a wide variety of cells of both vertebrate and insect origin and are widely used for the expression of heterologous genetic information both in vivo and in vitro. in spite of their use in a range of research applications and their recognition as a public health threat, the biology of alphaviruses is insufficiently understood. in this study, we ...201323365438
identification of a candidate therapeutic autophagy-inducing peptide.the lysosomal degradation pathway of autophagy has a crucial role in defence against infection, neurodegenerative disorders, cancer and ageing. accordingly, agents that induce autophagy may have broad therapeutic applications. one approach to developing such agents is to exploit autophagy manipulation strategies used by microbial virulence factors. here we show that a peptide, tat-beclin 1-derived from a region of the autophagy protein, beclin 1, which binds human immunodeficiency virus (hiv)-1 ...201323364696
o'nyong nyong virus molecular determinants of unique vector specificity reside in non-structural protein 3.o'nyong nyong virus (onnv) and chikungunya virus (chikv) are two closely related alphaviruses with very different infection patterns in the mosquito, anopheles gambiae. onnv is the only alphavirus transmitted by anopheline mosquitoes, but specific molecular determinants of infection of this unique vector specificity remain unidentified. fifteen distinct chimeric viruses were constructed to evaluate both structural and non-structural regions of the genome and infection patterns were determined th ...201323359824
differential unfolded protein response during chikungunya and sindbis virus infection: chikv nsp4 suppresses eif2α phosphorylation.chikungunya (chikv) and sindbis (sinv) are arboviruses belonging to the alphavirus genus within the togaviridae family. they cause frequent epidemics of febrile illness and long-term arthralgic sequelae that affect millions of people each year. both viruses replicate prodigiously in infected patients and in vitro in mammalian cells, suggesting some level of control over the host cellular translational machinery that senses and appropriately directs the cell's fate through the unfolded protein re ...201323356742
mcpip1 ribonuclease exhibits broad-spectrum antiviral effects through viral rna binding and degradation.monocyte chemoattractant protein 1-induced protein 1 (mcpip1), belonging to the mcpip family with highly conserved ccch-type zinc finger and nedd4-bp1, yacp nuclease domains, has been implicated in negative regulation of the cellular inflammatory responses. in this report, we demonstrate for the first time that this rna-binding nuclease also targets viral rna and possesses potent antiviral activities. overexpression of the human mcpip1, but not mcpip2, mcpip3 or mcpip4, inhibited japanese enceph ...201323355615
ires-based venezuelan equine encephalitis vaccine candidate elicits protective immunity in mice.venezuelan equine encephalitis virus (veev) is an arbovirus that causes periodic outbreaks that impact equine and human populations in the americas. one of the veev subtypes located in mexico and central america (ie) has recently been recognized as an important cause of equine disease and death, and human exposure also appears to be widespread. here, we describe the use of an internal ribosome entry site (ires) from encephalomyocarditis virus to stably attenuate veev, creating a vaccine candidat ...201323351391
host cell factors in filovirus entry: novel players, new insights.filoviruses cause severe hemorrhagic fever in humans with high case-fatality rates. the cellular factors exploited by filoviruses for their spread constitute potential targets for intervention, but are incompletely defined. the viral glycoprotein (gp) mediates filovirus entry into host cells. recent studies revealed important insights into the host cell molecules engaged by gp for cellular entry. the binding of gp to cellular lectins was found to concentrate virions onto susceptible cells and mi ...023342362
a chimeric sindbis-based vaccine protects cynomolgus macaques against a lethal aerosol challenge of eastern equine encephalitis virus.eastern equine encephalitis virus (eeev) is a mosquito-borne alphavirus that causes sporadic, often fatal disease outbreaks in humans and equids, and is also a biological threat agent. two chimeric vaccine candidates were constructed using a cdna clone with a sindbis virus (sinv) backbone and structural protein genes from either a north (sin/naeeev) or south american (sin/saeeev) strain of eeev. the vaccine candidates were tested in a nonhuman primate (nhp) model of eastern equine encephalitis ( ...201323333212
transgene-mediated suppression of the rna interference pathway in aedes aegypti interferes with gene silencing and enhances sindbis virus and dengue virus type 2 replication.rna interference (rnai) is the major innate antiviral pathway in aedes aegypti that responds to replicating arboviruses such as dengue virus (denv) and sindbis virus (sinv). on the one hand, the mosquito's rnai machinery is capable of completely eliminating denv2 from ae. aegypti. on the other, transient silencing of key genes of the rnai pathway increases replication of sinv and denv2, allowing the viruses to temporally overcome dose-dependent midgut infection and midgut escape barriers (meb) m ...023331493
visualizing the autophagy pathway in avian cells and its application to studying infectious bronchitis virus.autophagy is a highly conserved cellular response to starvation that leads to the degradation of organelles and long-lived proteins in lysosomes and is important for cellular homeostasis, tissue development and as a defense against aggregated proteins, damaged organelles and infectious agents. although autophagy has been studied in many animal species, reagents to study autophagy in avian systems are lacking. microtubule-associated protein 1 light chain 3 (map1lc3/lc3) is an important marker for ...201323328491
retargeting vesicular stomatitis virus glycoprotein pseudotyped lentiviral vectors with enhanced stability by in situ synthesized polymer shell.the ability to introduce transgenes with precise specificity to the desired target cells or tissues is key to a more facile application of genetic therapy. here, we describe a novel method using nanotechnology to generate lentiviral vectors with altered recognition of host cell receptor specificity. briefly, the infectivity of the vesicular stomatitis virus glycoprotein (vsv-g) pseudotyped lentiviral vectors was shielded by a thin polymer shell synthesized in situ onto the viral envelope, and ne ...023327104
sumoylation is required for glycine-induced increases in ampa receptor surface expression (chemltp) in hippocampal neurons.multiple pathways participate in the ampa receptor trafficking that underlies long-term potentiation (ltp) of synaptic transmission. here we demonstrate that protein sumoylation is required for insertion of the glua1 ampar subunit following transient glycine-evoked increase in ampa receptor surface expression (chemltp) in dispersed neuronal cultures. chemltp increases co-localisation of sumo-1 and the sumo conjugating enzyme ubc9 and with psd95 consistent with the recruitment of sumoylated prote ...201323326329
a key interaction between the alphavirus envelope proteins responsible for initial dimer dissociation during fusion.alphaviruses such as semliki forest virus (sfv) are enveloped viruses whose surface is covered by an organized lattice composed of trimers of e2-e1 heterodimers. the e1 envelope protein, a class ii fusion protein, contains the hydrophobic fusion loop and refolds to drive virus fusion with the endosome membrane. the e2 protein is synthesized as a precursor p62, whose processing by furin primes the heterodimer for dissociation during virus entry. dissociation of the e2-e1 heterodimer is an essenti ...201323325694
polio, still lurking in the shadows. 023325224
small creatures use small rnas to direct antiviral defenses.antiviral rna silencing has been recognized as an important defense mechanism in arthropods against rna viruses. however, the role of this pathway in dna virus infection remains largely unexplored. a report in this issue of the european journal of immunology provides new insight into the role of rna silencing in antiviral defense against dna viruses. huang and zhang [eur. j. immunol. 2013. 137-146] found that the dsdna virus white spot syndrome virus, an agriculturally important pathogen of shri ...023322691
crystal structure of glycoprotein c from rift valley fever virus.rift valley fever virus (rvfv), like many other bunyaviridae family members, is an emerging human and animal pathogen. bunyaviruses have an outer lipid envelope bearing two glycoproteins, g(n) and g(c), required for cell entry. bunyaviruses deliver their genome into the host-cell cytoplasm by fusing their envelope with an endosomal membrane. the molecular mechanism of this key entry step is unknown. the crystal structure of rvfv g(c) reveals a class ii fusion protein architecture found previousl ...201323319635
macrophages, inflammation, and tumor suppressors: arf, a new player in the game.the interaction between tumor progression and innate immune system has been well established in the last years. indeed, several lines of clinical evidence indicate that immune cells such as tumor-associated macrophages (tams) interact with tumor cells, favoring growth, angiogenesis, and metastasis of a variety of cancers. in most tumors, tams show properties of an alternative polarization phenotype (m2) characterized by the expression of a series of chemokines, cytokines, and proteases that prom ...201223316105
ifn production ability and healthy ageing: mixed model analysis of a 24 year longitudinal study in japan.to track changes in interferon (ifn) production in healthy individuals to shed light on the effect these changes have on the course of healthy ageing.201323315513
mossy fiber-ca3 synapses mediate homeostatic plasticity in mature hippocampal neurons.network activity homeostatically alters synaptic efficacy to constrain neuronal output. however, it is unclear how such compensatory adaptations coexist with synaptic information storage, especially in established networks. here, we report that in mature hippocampal neurons in vitro, network activity preferentially regulated excitatory synapses within the proximal dendrites of ca3 neurons. these homeostatic synapses exhibited morphological, functional, and molecular signatures of the specialized ...023312519
dna prime-protein boost strategy with replicase-based dna vaccine against foot-and-mouth disease in bovine calves.the limited efficacy of dna vaccines against foot-and-mouth disease (fmd) in cattle and other natural hosts has prompted a search for a more effective vaccination regimen. in this study we tested a dna prime-protein boost vaccination strategy against fmd in bovine calves. we used purified recombinant fmdv specific multi-epitope protein (rmeg990) and an optimized sindbis virus replicase-based dna vaccine expressing this protein (psincmv-vac-meg990). we demonstrate that vaccination with a low dose ...201223305616
astrocyte-derived cxcl10 drives accumulation of antibody-secreting cells in the central nervous system during viral encephalomyelitis.microbial infections of the central nervous system (cns) are often associated with local accumulation of antibody (ab)-secreting cells (asc). by providing a source of ab at the site of infection, cns-localized asc play a critical role in acute viral control and in preventing viral recrudescence. following coronavirus-induced encephalomyelitis, the cns accumulation of asc is chemokine (c-x-c motif) receptor 3 (cxcr3) dependent. this study demonstrates that cns-expressed cxcr3 ligand cxcl10 is the ...201323302888
filoviruses utilize glycosaminoglycans for their attachment to target cells.filoviruses are the cause of severe hemorrhagic fever in human and nonhuman primates. the envelope glycoprotein (gp), responsible for both receptor binding and fusion of the virus envelope with the host cell membrane, has been demonstrated to interact with multiple molecules in order to enhance entry into host cells. here we have demonstrated that filoviruses utilize glycosaminoglycans, and more specifically heparan sulfate proteoglycans, for their attachment to host cells. this interaction is m ...201323302881
predictors of chikungunya rheumatism: a prognostic survey ancillary to the telechik cohort study.long-lasting relapsing or lingering rheumatic musculoskeletal pain (rmsp) is the hallmark of chikungunya virus (chikv) rheumatism (chik-r). little is known on their prognostic factors. the aim of this prognostic study was to search the determinants of lingering or relapsing rmsp indicative of chik-r.201323302155
bioluminescent imaging and histopathologic characterization of weev neuroinvasion in outbred cd-1 mice.western equine encephalitis virus (weev; alphavirus) is a mosquito-borne virus that can cause severe encephalitis in humans and equids. previous studies have shown that intranasal infection of outbred cd-1 mice with the weev mcmillan (mcm) strain result in high mortality within 4 days of infection. here in vivo and ex vivo bioluminescence (blm) imaging was applied on mice intranasally infected with a recombinant mcm virus expressing firefly luciferase (fluc) to track viral neuroinvasion by fluc ...201323301074
human papillomavirus infection is inhibited by host autophagy in primary human keratinocytes.human papillomavirus (hpv) infection is severely limited in its natural host, primary human keratinocytes. our data show hpv infectivity in primary keratinocytes is over 100- and 1,000-fold lower than in established keratinocyte cell lines niks and hacat, respectively. here, we show that the basal level of autophagy in primary human foreskin keratinocytes (hfks) is higher than in immortalized keratinocytes, and that hpv16 virions significantly induce autophagy in hfks. interestingly, hpv16 infec ...201323290079
novel vaccine against venezuelan equine encephalitis combines advantages of dna immunization and a live attenuated vaccine.dna vaccines combine remarkable genetic and chemical stability with proven safety and efficacy in animal models, while remaining less immunogenic in humans. in contrast, live-attenuated vaccines have the advantage of inducing rapid, robust, long-term immunity after a single-dose vaccination. here we describe novel idna vaccine technology that is based on an infectious dna platform and combines advantages of dna and live attenuated vaccines. we applied this technology for vaccination against infe ...201223287629
5-(perylen-3-yl)ethynyl-arabino-uridine (auy11), an arabino-based rigid amphipathic fusion inhibitor, targets virion envelope lipids to inhibit fusion of influenza virus, hepatitis c virus, and other enveloped viruses.entry of enveloped viruses requires fusion of viral and cellular membranes. fusion requires the formation of an intermediate stalk structure, in which only the outer leaflets are fused. the stalk structure, in turn, requires the lipid bilayer of the envelope to bend into negative curvature. this process is inhibited by enrichment in the outer leaflet of lipids with larger polar headgroups, which favor positive curvature. accordingly, phospholipids with such shape inhibit viral fusion. we previou ...201323283943
inhibition of chikungunya virus replication by harringtonine, a novel antiviral that suppresses viral protein expression.chikungunya virus (chikv) is a mosquito-transmitted virus that has reemerged as a significant public health threat in the last decade. since the 2005-2006 chikungunya fever epidemic in the indian ocean island of la réunion, millions of people in more than 40 countries have been infected. despite this, there is currently no antiviral treatment for chikungunya infection. in this study, an immunofluorescence-based screening platform was developed to identify potential inhibitors of chikv infection. ...201223275491
interplay between viruses and host mrna degradation.messenger rna degradation is a fundamental cellular process that plays a critical role in regulating gene expression by controlling both the quality and the abundance of mrnas in cells. naturally, viruses must successfully interface with the robust cellular rna degradation machinery to achieve an optimal balance between viral and cellular gene expression and establish a productive infection in the host. in the past several years, studies have discovered many elegant strategies that viruses have ...201223274304
construction and organization of a bsl-3 cryo-electron microscopy laboratory at utmb.a unique cryo-electron microscopy facility has been designed and constructed at the university of texas medical branch (utmb) to study the three-dimensional organization of viruses and bacteria classified as select agents at biological safety level (bsl)-3, and their interactions with host cells. a 200kev high-end cryo-electron microscope was installed inside a bsl-3 containment laboratory and standard operating procedures were developed and implemented to ensure its safe and efficient operation ...201223274136
structure of a pestivirus envelope glycoprotein e2 clarifies its role in cell entry.enveloped viruses have developed various adroit mechanisms to invade their host cells. this process requires one or more viral envelope glycoprotein to achieve cell attachment and membrane fusion. members of the flaviviridae such as flaviviruses possess only one envelope glycoprotein, e, whereas pestiviruses and hepacivirus encode two glycoproteins, e1 and e2. although e2 is involved in cell attachment, it has been unclear which protein is responsible for membrane fusion. we report the crystal s ...201223273918
the feline calicivirus leader of the capsid protein is associated with cytopathic effect.open reading frame 2 (orf2) of the feline calicivirus (fcv) genome encodes a capsid precursor that is posttranslationally processed to release the mature capsid protein (vp1) and a small protein of 124 amino acids, designated the leader of the capsid (lc). to investigate the role of the lc protein in the virus life cycle, mutations and deletions were introduced into the lc coding region of an infectious fcv cdna clone. three cysteine residues that are conserved among all vesivirus lc sequences w ...201223269802
rna interference targets arbovirus replication in culicoides cells.arboviruses are transmitted to vertebrate hosts by biting arthropod vectors such as mosquitoes, ticks, and midges. these viruses replicate in both arthropods and vertebrates and are thus exposed to different antiviral responses in these organisms. rna interference (rnai) is a sequence-specific rna degradation mechanism that has been shown to play a major role in the antiviral response against arboviruses in mosquitoes. culicoides midges are important vectors of arboviruses, known to transmit pat ...201223269795
boosting the immune response: the use of inkt cell ligands as vaccine adjuvants.natural killer t (nkt) cells comprise a small, but important t cell subset and are thought to bridge the innate and adaptive immune responses. the discovery of nkt cells and extensive research on their activating ligands have paved the way for modulation of these potent immunoregulatory cells in order to improve the outcome of various clinical conditions. efforts to modulate nkt cell effector functions have ranged from therapy for influenza to anti-tumor immunotherapy. these approaches have also ...201223264781
zap inhibits murine gammaherpesvirus 68 orf64 expression and is antagonized by rta.zinc finger antiviral protein (zap) is an interferon-inducible host antiviral factor that specifically inhibits the replication of certain viruses, including hiv-1 and ebola virus. zap functions as a dimer formed through intermolecular interactions of its n-terminal tails. zap binds directly to specific viral mrnas and inhibits their expression by repressing translation and/or promoting degradation of the target mrna. zap is not a universal antiviral factor, since some viruses grow normally in z ...201223255809
recruitment and retention of b cells in the central nervous system in response to alphavirus encephalomyelitis.sindbis virus (sinv) infection of neurons results in nonfatal viral encephalomyelitis and provides a model system for understanding recovery from virus infection of the central nervous system (cns). infection is followed by clearance of infectious virus, a gradual decrease in viral rna, and then long-term maintenance of low levels of viral rna. antibody to the e2 glycoprotein is important for virus clearance, and b cells enter the cns along with cd4(+) and cd8(+) t cells during the early clearan ...201223255791
phosphorylation of eif2α is responsible for the failure of the picornavirus internal ribosome entry site to direct translation from sindbis virus replicons.translation directed by the poliovirus (pv) or encephalomyocarditis virus (emcv) internal ribosome entry site (ires) is very inefficient when expressed from sindbis virus (sv) replicons. this inhibition can be rescued by co-expression of pv 2a protease (2a(pro)). inhibition correlates with the extensive phosphorylation of eukaryotic initiation factor (eif) 2α induced by sv replication. confirmation that pv or emcv ires-driven translation can function when eif2α is not phosphorylated was obtained ...201323255624
broad rna interference-mediated antiviral immunity and virus-specific inducible responses in drosophila.the fruit fly drosophila melanogaster is a good model to unravel the molecular mechanisms of innate immunity and has led to some important discoveries about the sensing and signaling of microbial infections. the response of drosophila to virus infections remains poorly characterized and appears to involve two facets. on the one hand, rna interference involves the recognition and processing of dsrna into small interfering rnas by the host rnase dicer-2 (dcr-2), whereas, on the other hand, an indu ...201223255357
mouse macrophage innate immune response to chikungunya virus infection.infection with chikungunya alphavirus (chikv) can cause severe arthralgia and chronic arthritis in humans with persistence of the virus in perivascular macrophages of the synovial membrane by mechanisms largely ill-characterized.201223253140
crystal structure of aura virus capsid protease and its complex with dioxane: new insights into capsid-glycoprotein molecular contacts.the nucleocapsid core interaction with endodomains of glycoproteins plays a critical role in the alphavirus life cycle that is essential to virus budding. recent cryo-electron microscopy (cryo-em) studies provide structural insights into key interactions between capsid protein (cp) and trans-membrane glycoproteins e1 and e2. cp possesses a chymotrypsin-like fold with a hydrophobic pocket at the surface responsible for interaction with glycoproteins. in the present study, crystal structures of th ...201223251484
induction of humoral and cellular immune responses against hepatitis c virus by vaccination with replicon particles derived from sindbis-like virus xj-160.a replication-defective, recombinant sindbis virus vector was utilized in a novel immunization strategy to induce humoral and cellular responses against hepatitis c virus (hcv). the recombinant vector, pvaxj-e1e2, expressing the gene for hcv glycoproteins e2 and e1, was constructed by inserting the e1e2 gene into the replicon pvaxj, a dna vector derived from sindbis-like virus xj-160. the defective replicon particles, xj-e1e2, were produced by transfecting bhk-21(e+capsid) cells, the packaging c ...201323250650
inflammatory monocytes and the pathogenesis of viral encephalitis.monocytes are a heterogeneous population of bone marrow-derived cells that are recruited to sites of infection and inflammation in many models of human diseases, including those of the central nervous system (cns). ly6chi/ccr2(hi) inflammatory monocytes have been identified as the circulating precursors of brain macrophages, dendritic cells and arguably microglia in experimental autoimmune encephalomyelitis; alzheimer's disease; stroke; and more recently in cns infection caused by herpes simplex ...201223244217
virotherapy, gene transfer and immunostimulatory monoclonal antibodies.malignant cells are susceptible to viral infection and consequent cell death. virus-induced cell death is endowed with features that are known to stimulate innate and adaptive immune responses. thus danger signals emitted by cells succumbing to viral infection as well as viral nucleic acids are detected by specific receptors, and tumor cell antigens can be routed to professional antigen-presenting cells. the anticancer immune response triggered by viral infection is frequently insufficient to er ...023243597
diversity in glycosaminoglycan binding amongst hmpv g protein lineages.we have previously shown that hmpv g protein (b2 lineage) interacts with cellular glycosaminoglycans (gags). in this study we examined subtypes a1, a2 and b1 for this interaction. gag-dependent infectivity of available hmpv strains was demonstrated using gag-deficient cells and heparin competition. we expressed the g protein ectodomains from all strains and analysed these by heparin affinity chromatography. in contrast to the b2 lineage, neither the a2 or b1 g proteins bound to heparin. sequence ...201223242371
replication of west nile virus, rabensburg lineage in mammalian cells is restricted by temperature.the genus flavivirus currently consists of approximately 80 single-strand positive-sense rna viruses. these replicate in a range of hosts including myriad vertebrate, insect, and tick species. as a consequence of this broad host range, the majority of flaviviruses can be propagated in most vertebrate and insect cell cultures. this ability to infect arthropods and vertebrates usually is essential for maintenance of these viruses in nature. but recently, there has been the discovery of a number of ...201223241081
immunization of mice with recombinant mosquito salivary protein d7 enhances mortality from subsequent west nile virus infection via mosquito bite.mosquito salivary proteins (msps) modulate the host immune response, leading to enhancement of arboviral infections. identification of proteins in saliva responsible for immunomodulation and counteracting their effects on host immune response is a potential strategy to protect against arboviral disease. we selected a member of the d7 protein family, which are among the most abundant and immunogenic in mosquito saliva, as a vaccine candidate with the aim of neutralizing effects on the mammalian i ...201223236530
hyperresponsiveness of mice deficient in plasma-secreted sphingomyelinase reveals its pivotal role in early phase of host response.plasma secretion of acid sphingomyelinase is a hallmark of cellular stress response resulting in the formation of membrane embedded ceramide-enriched lipid rafts and the reorganization of receptor complexes. consistently, decompartmentalization of ceramide formation from inert sphingomyelin has been associated with signaling events and regulation of the cellular phenotype. herein, we addressed the question of whether the secretion of acid sphingomyelinase is involved in host response during seps ...201223230083
reminiscence of our research on membrane phospholipids in mammalian cells by using the novel technology.by using "our devised up-to-the-second technique" over 30 years ago, we succeeded in the first isolation in the world of the three different kinds of mammalian cell mutants defective in the biosynthesis on each of phosphatidylserine (ps), cardiolipin (cl) and sphingomyelin (sm) from the parental cho cells. as the results, we found that during the biosyntheses of ps and sm, the biosynthetic precursor or the final lipids are transported from their synthesized intracellular organelles to the plasma ...023229749
activation of double-stranded rna-activated protein kinase (pkr) by interferon-stimulated gene 15 (isg15) modification down-regulates protein translation.the ubiquitin-like molecule isg15 (ucrp) and protein modification by isg15 (isgylation) are strongly induced by interferon, genotoxic stress, and pathogen infection, suggesting that isg15 plays an important role in innate immune responses. however, how isgylation contributes to innate immune responses is not clear. the dsrna-dependent protein kinase (pkr) inhibits translation by phosphorylating eif2α to exert its anti-viral effect. isg15 and pkr are induced by interferon, suggesting that a relat ...201223229543
screening of dengue virus antiviral activity of marine seaweeds by an in situ enzyme-linked immunosorbent assay.dengue is a significant public health problem worldwide. despite the important social and clinical impact, there is no vaccine or specific antiviral therapy for prevention and treatment of dengue virus (denv) infection. considering the above, drug discovery research for dengue is of utmost importance; in addition natural marine products provide diverse and novel chemical structures with potent biological activities that must be evaluated. in this study we propose a target-free approach for dengu ...201223227238
release of dengue virus genome induced by a peptide inhibitor.dengue virus infects approximately 100 million people annually, but there is no available therapeutic treatment. the mimetic peptide, dn59, consists of residues corresponding to the membrane interacting, amphipathic stem region of the dengue virus envelope (e) glycoprotein. this peptide is inhibitory to all four serotypes of dengue virus, as well as other flaviviruses. cryo-electron microscopy image reconstruction of dengue virus particles incubated with dn59 showed that the virus particles were ...201223226444
hypervariable domains of nsp3 proteins of new world and old world alphaviruses mediate formation of distinct, virus-specific protein complexes.alphaviruses are a group of single-stranded rna viruses with genomes of positive polarity. they are divided into two geographically isolated groups: the old world and the new world alphaviruses. despite their similar genome organizations and virion structures, they differ in many aspects of pathogenesis and interaction with the host cell. here we present new data highlighting previously unknown differences between these two groups. we found that nsp3 proteins of sindbis virus (sinv) and venezuel ...201223221551
pseudoinfectious venezuelan equine encephalitis virus: a new means of alphavirus attenuation.venezuelan equine encephalitis virus (veev) is a reemerging virus that causes a severe and often fatal disease in equids and humans. in spite of a continuous public health threat, to date, no vaccines or antiviral drugs have been developed for human use. experimental vaccines demonstrate either poor efficiency or severe adverse effects. in this study, we developed a new strategy of alphavirus modification aimed at making these viruses capable of replication and efficient induction of the immune ...201223221545
inhibitory effects of crude extracts from some edible thai plants against replication of hepatitis b virus and human liver cancer cells.edible plants such as cratoxylum formosum (jack) dyer, curcumin longa lin, momordica charantia lin and moringa oleifera lam have long been believed in thai culture to relieve ulcers and the symptoms of liver disease. however, little is known about their anti-liver cancer properties and antiviral activity against hepatitis b virus (hbv). the aim of this study was to investigate the anti-liver cancer and anti-hbv activities of crude extracts from these edible plants on human liver cancer cells.201223216691
prostratin and 12-o-tetradecanoylphorbol 13-acetate are potent and selective inhibitors of chikungunya virus replication.a chemical study of the vietnamese plant species trigonostemon howii led to the isolation of a new tigliane-type diterpenoid, trigowiin a (1), along with several known coumarins and phenylpropanoids. the planar structure and the relative configuration of compound 1 were elucidated based on spectroscopic analysis, including 1d- and 2d-nmr experiments, mass spectrometry, and comparison with literature data. trigowiin a (1) exhibited moderate antiviral activity in a virus-cell-based assay for chiku ...201223215460
complex modulation of the aedes aegypti transcriptome in response to dengue virus infection.dengue fever is the most important arboviral disease world-wide, with aedes aegypti being the major vector. interactions between the mosquito host and dengue viruses (denv) are complex and vector competence varies among geographically-distinct ae. aegypti populations. additionally, dengue is caused by four antigenically-distinct viral serotypes (denv1-4), each with multiple genotypes. each virus genotype interacts differently with vertebrate and invertebrate hosts. analyses of alterations in mos ...201223209765
genotypic and phenotypic characterization of chikungunya virus of different genotypes from malaysia.mosquito-borne chikungunya virus (chikv) has recently re-emerged globally. the epidemic east/central/south african (ecsa) strains have spread for the first time to asia, which previously only had endemic asian strains. in malaysia, the ecsa strain caused an extensive nationwide outbreak in 2008, while the asian strains only caused limited outbreaks prior to this. to gain insight into these observed epidemiological differences, we compared genotypic and phenotypic characteristics of chikv of asia ...201223209750
il-1β signaling promotes cns-intrinsic immune control of west nile virus infection.west nile virus (wnv) is an emerging flavivirus capable of infecting the central nervous system (cns) and mediating neuronal cell death and tissue destruction. the processes that promote inflammation and encephalitis within the cns are important for control of wnv disease but, how inflammatory signaling pathways operate to control cns infection is not defined. here, we identify il-1β signaling and the nlrp3 inflammasome as key host restriction factors involved in viral control and cns disease as ...201223209411
tinkering with translation: protein synthesis in virus-infected cells.viruses are obligate intracellular parasites, and their replication requires host cell functions. although the size, composition, complexity, and functions encoded by their genomes are remarkably diverse, all viruses rely absolutely on the protein synthesis machinery of their host cells. lacking their own translational apparatus, they must recruit cellular ribosomes in order to translate viral mrnas and produce the protein products required for their replication. in addition, there are other con ...201323209131
cell-type specific requirements for thiol/disulfide exchange during hiv-1 entry and infection.the role of disulfide bond remodeling in hiv-1 infection is well described, but the process still remains incompletely characterized. at present, the data have been predominantly obtained using established cell lines and/or cxcr4-tropic laboratory-adapted virus strains. there is also ambiguity about which disulfide isomerases/reductases play a major role in hiv-1 entry, as protein disulfide isomerase (pdi) and/or thioredoxin (trx) have emerged as the two enzymes most often implicated in this pro ...201223206338
involvement of autophagy in coronavirus replication.coronaviruses are single stranded, positive sense rna viruses, which induce the rearrangement of cellular membranes upon infection of a host cell. this provides the virus with a platform for the assembly of viral replication complexes, improving efficiency of rna synthesis. the membranes observed in coronavirus infected cells include double membrane vesicles. by nature of their double membrane, these vesicles resemble cellular autophagosomes, generated during the cellular autophagy pathway. in a ...201223202545
dsrna-dependent protein kinase pkr and its role in stress, signaling and hcv infection.the double-stranded rna-dependent protein kinase pkr plays multiple roles in cells, in response to different stress situations. as a member of the interferon (ifn)‑stimulated genes, pkr was initially recognized as an actor in the antiviral action of ifn, due to its ability to control translation, through phosphorylation, of the alpha subunit of eukaryotic initiation factor 2 (eif2a). as such, pkr participates in the generation of stress granules, or autophagy and a number of viruses have designe ...201223202496
hepatitis c virus and cellular stress response: implications to molecular pathogenesis of liver diseases.infection with hepatitis c virus (hcv) is a leading risk factor for chronic liver disease progression, including steatosis, cirrhosis, and hepatocellular carcinoma. with approximately 3% of the human population infected worldwide, hcv infection remains a global public health challenge. the efficacy of current therapy is still limited in many patients infected with hcv, thus a greater understanding of pathogenesis in hcv infection is desperately needed. emerging lines of evidence indicate that hc ...201223202463
drivers, dynamics, and control of emerging vector-borne zoonotic diseases.emerging vector-borne diseases are an important issue in global health. many vector-borne pathogens have appeared in new regions in the past two decades, while many endemic diseases have increased in incidence. although introductions and emergence of endemic pathogens are often considered to be distinct processes, many endemic pathogens are actually spreading at a local scale coincident with habitat change. we draw attention to key differences between dynamics and disease burden that result from ...201223200503
antiviral activity of a derivative of the photosensitive compound hypericin.eight synthetic compounds related to the photosensitive antiviral quinonic plant compound hypericin were screened for light-mediated antiviral activity. the compound 2,5,9,12-tetra(carboxyethylthiomethyl) hypericin was found to have activity against membrane-enveloped sindbis virus and murine cytomegalovirus but not against the non-enveloped poliovirus. the activity of this compound was investigated in more detail. the mechanism of action appeared to be of the photosensitive singlet oxygen type ...199623194968
specificity of resistance to dengue virus isolates is associated with genotypes of the mosquito antiviral gene dicer-2.in contrast to the prevailing view that invertebrate immunity relies on broad-spectrum recognition and effector mechanisms, intrinsic genetic compatibility between invertebrate hosts and their pathogens is often highly specific in nature. solving this puzzle requires a better understanding of the molecular basis underlying observed patterns of invertebrate host-pathogen genetic specificity, broadly referred to as genotype-by-genotype interactions. here, we identify an invertebrate immune gene in ...023193131
the gef1 proton-chloride exchanger affects tombusvirus replication via regulation of copper metabolism in yeast.replication of plus-strand rna viruses [(+)rna viruses] is performed by viral replicases, whose function is affected by many cellular factors in infected cells. in this paper, we demonstrate a surprising role for gef1p proton-chloride exchanger in replication of tomato bushy stunt virus (tbsv) model (+)rna virus. a genetic approach revealed that gef1p, which is the only proton-chloride exchanger in saccharomyces cerevisiae, is required for tbsv replication in the yeast model host. we also show t ...201223192874
requirements for eif4a and eif2 during translation of sindbis virus subgenomic mrna in vertebrate and invertebrate host cells.we have examined the requirements for the initiation factors (eifs) eif4a and eif2 to translate sindbis virus (sv) subgenomic mrna (sgmrna) in the natural hosts of sv: vertebrate and arthropod cells. notably, this viral mrna does not utilize eif4a in sv-infected mammalian cells. however, eif4a is required to translate this mrna in transfected cells. therefore, sv sgmrna exhibits a dual mechanism for translation with respect to the use of eif4a. interestingly, sv genomic mrna requires eif4a for t ...201323189929
prime-boost approaches to tuberculosis vaccine development.four individuals die from active tb disease each minute, while at least 2 billion are latently infected and at risk for disease reactivation. bcg, the only licensed tb vaccine, is effective in preventing childhood forms of tb; however its poor efficacy in adults, emerging drug-resistant tb strains and tedious chemotherapy regimes, warrant the development of novel prophylactic measures. designing safe and effective vaccines against tb will require novel approaches on several levels, including the ...023176655
reverse transcription loop-mediated isothermal amplification for rapid detection of japanese encephalitis virus in swine and mosquitoes.japanese encephalitis (je) can infect many agriculturally important animals and humans, and has a high incidence in asia. one of the natural hosts of the mosquito-borne je virus (jev) is domestic pigs, which act as amplifier hosts. porcine infection results in fatal encephalitis, abortion, and stillbirth in pregnant sows, and hypospermia in boars. in this study, a rapid jev detection method for swine and mosquitoes was developed based on reverse transcription loop-mediated isothermal amplificati ...201223176446
dicer-2- and piwi-mediated rna interference in rift valley fever virus-infected mosquito cells.rift valley fever virus (rvfv) is a phlebovirus (bunyaviridae family) transmitted by mosquitoes. it infects humans and ruminants, causing dramatic epidemics and epizootics in africa, yemen, and saudi arabia. while recent studies demonstrated the importance of the nonstructural protein nss as a major component of virulence in vertebrates, little is known about infection of mosquito vectors. here we studied rvfv infection in three different mosquito cell lines, aag2 cells from aedes aegypti and u4 ...201223175368
a new rabies vaccine based on a recombinant orf virus (parapoxvirus) expressing the rabies virus glycoprotein.the present study describes the generation of a new orf virus (orfv) recombinant, d1701-v-rabg, expressing the rabies virus (rabv) glycoprotein that is correctly presented on the surface of infected cells without the need of replication or production of infectious recombinant virus. one single immunization with recombinant orfv can stimulate high rabv-specific virus-neutralizing antibody (vna) titers in mice, cats, and dogs, representing all nonpermissive hosts for the orfv vector. the protectiv ...201223175365
reemergence of chikungunya virus in cambodia.chikungunya virus (chikv), probably asian genotype, was first detected in cambodia in 1961. despite no evidence of acute or recent chikv infections since 2000, real-time reverse transcription pcr of serum collected in 2011 detected chikv, east central south african genotype. spatiotemporal patterns and phylogenetic clustering indicate that the virus probably originated in thailand.023171736
west nile virus neurologic disease in humans, south africa, september 2008-may 2009.we investigated west nile virus (wnv) as a possible disease etiology in persons hospitalized in south africa. of 206 specimens tested, 36 had wnv neutralizing antibodies, significantly more than in similar earlier serosurveys. seven probable acute wnv cases were identified, suggesting wnv may be overlooked as an etiology of severe disease in south africa.201223171668
potential vaccines and post-exposure treatments for filovirus infections.viruses of the family filoviridae represent significant health risks as emerging infectious diseases as well as potentially engineered biothreats. while many research efforts have been published offering possibilities toward the mitigation of filoviral infection, there remain no sanctioned therapeutic or vaccine strategies. current progress in the development of filovirus therapeutics and vaccines is outlined herein with respect to their current level of testing, evaluation, and proximity toward ...201223170176
climatic, ecological and socioeconomic factors as predictors of sindbis virus infections in finland.mosquito-borne sindbis virus (sinv) causes rash-arthritis syndrome in finland. major outbreaks with approximately 7-year cycles have caused substantial burden of illness. forest dwelling grouse are suspected to be amplifying hosts, with the infection transmitted to humans by mosquito bites. sinv infection surveillance data for 1984–2010 were used to create a negative binomial hurdle model, with seasonality, long-term cycles, climatic, ecological and socioeconomic variables. climatic factors duri ...201323158410
proteomics-based methods for discovery, quantification, and validation of protein-protein interactions. 201223157382
infection by chikungunya virus modulates the expression of several proteins in aedes aegypti salivary glands.arthropod-borne viral infections cause several emerging and resurging infectious diseases. among the diseases caused by arboviruses, chikungunya is responsible for a high level of severe human disease worldwide. the salivary glands of mosquitoes are the last barrier before pathogen transmission.201223153178
demographic consequences of predators on prey: trait and density mediated effects on mosquito larvae in containers.predators may affect prey population growth and community diversity through density mediated lethal and trait mediated non-lethal effects that influence phenotypic traits of prey. we tested experimentally the roles of thinning the density of prey (lethality) in the absence of predator cues and density and trait mediated effects (lethality + intimidation) of predatory midge corethrella appendiculata on competing native and invasive mosquito prey. predator-mediated reductions in prey and density r ...201223152748
the dna virus invertebrate iridescent virus 6 is a target of the drosophila rnai machinery.rna viruses in insects are targets of an rna interference (rnai)-based antiviral immune response, in which viral replication intermediates or viral dsrna genomes are processed by dicer-2 (dcr-2) into viral small interfering rnas (vsirnas). whether dsdna virus infections are controlled by the rnai pathway remains to be determined. here, we analyzed the role of rnai in dna virus infection using drosophila melanogaster infected with invertebrate iridescent virus 6 (iiv-6) as a model. we show that d ...201223151511
chikungunya virus and prospects for a vaccine.in 2004, chikungunya virus (chikv) re-emerged from east africa to cause devastating epidemics of debilitating and often chronic arthralgia that have affected millions of people in the indian ocean basin and asia. more limited epidemics initiated by travelers subsequently occurred in italy and france, as well as human cases exported to most regions of the world, including the americas where chikv could become endemic. because chikv circulates during epidemics in an urban mosquito-human cycle, con ...023151166
phenoloxidase activity acts as a mosquito innate immune response against infection with semliki forest virus.several components of the mosquito immune system including the rna interference (rnai), jak/stat, toll and imd pathways have previously been implicated in controlling arbovirus infections. in contrast, the role of the phenoloxidase (po) cascade in mosquito antiviral immunity is unknown. here we show that conditioned medium from the aedes albopictus-derived u4.4 cell line contains a functional po cascade, which is activated by the bacterium escherichia coli and the arbovirus semliki forest virus ...201223144608
targeted treatments for cervical cancer: a review.cervical cancer is the second most common cause of cancer death in women worldwide and the development of new diagnosis, prognostic, and treatment strategies merits special attention. although surgery and chemoradiotherapy can cure 80%-95% of women with early stage cancer, the recurrent and metastatic disease remains a major cause of cancer death. many efforts have been made to design new drugs and develop gene therapies to treat cervical cancer. in recent decades, research on treatment strategi ...201223144564
modulation of hepatitis c virus rna abundance and virus release by dispersion of processing bodies and enrichment of stress granules.components of cytoplasmic processing bodies (p-bodies) and stress granules can be subverted during viral infections to modulate viral gene expression. because hepatitis c virus (hcv) rna abundance is regulated by p-body components such as microrna mir-122, argonaute 2 and rna helicase rck/p54, we examined whether hcv infection modulates p-bodies and stress granules during viral infection. it was discovered that hcv infection decreased the number of p-bodies, but induced the formation of stress g ...201223141719
dendritic cell-directed vaccination with a lentivector encoding psca for prostate cancer in mice.many studies have demonstrated that prostate stem cell antigen (psca) is an attractive target for immunotherapy based on its overexpression in prostate tumor tissue, especially in some metastatic tissues. in this study, we evaluated dendritic cell (dc)-directed lentiviral vector (dclv) encoding murine psca (dclv-psca) as a novel tumor vaccine for prostate cancer in mouse models. we showed that dclv-psca could preferentially deliver the psca antigen gene to dc-sign-expressing 293t cells and bone ...201223139820
the folded and disordered domains of human ribosomal protein sa have both idiosyncratic and shared functions as membrane receptors.the human rpsa [ribosomal protein sa; also known as lamr1(laminin receptor 1)] belongs to the ribosome but is also a membrane receptor for laminin, growth factors, prion, pathogens and the anticarcinogen egcg (epigallocatechin-gallate). it contributes to the crossing of the blood-brain barrier by neurotropic viruses and bacteria, and is a biomarker of metastasis. rpsa includes an n-terminal domain, which is folded and homologous to the prokaryotic rps2, and a c-terminal extension, which is intri ...201223137297
dugbe virus ovarian tumour domain interferes with ubiquitin/isg15-regulated innate immune cell signalling.the ovarian tumour (otu) domain of the nairovirus l protein has been shown to remove ubiquitin and interferon-stimulated gene 15 protein (isg15) from host cell proteins, which is expected to have multiple effects on cell signalling pathways. we have confirmed that the otu domain from the l protein of the apathogenic nairovirus dugbe virus has deubiquitinating and deisgylating activity and shown that, when expressed in cells, it is highly effective at blocking the tnf-α/nf-κb and interferon/jak/s ...201223136361
host mtorc1 signaling regulates andes virus replication.hantavirus pulmonary syndrome (hps) is a severe respiratory disease characterized by pulmonary edema, with fatality rates of 35 to 45%. disease occurs following infection with pathogenic new world hantaviruses, such as andes virus (andv), which targets lung microvascular endothelial cells. during replication, the virus scavenges 5'-m(7)g caps from cellular mrna to ensure efficient translation of viral proteins by the host cell cap-dependent translation machinery. in cells, the mammalian target o ...201223135723
impact of wolbachia on infection with chikungunya and yellow fever viruses in the mosquito vector aedes aegypti.incidence of disease due to dengue (denv), chikungunya (chikv) and yellow fever (yfv) viruses is increasing in many parts of the world. the viruses are primarily transmitted by aedes aegypti, a highly domesticated mosquito species that is notoriously difficult to control. when transinfected into ae. aegypti, the intracellular bacterium wolbachia has recently been shown to inhibit replication of denvs, chikv, malaria parasites and filarial nematodes, providing a potentially powerful biocontrol st ...201223133693
gene expression studies of host response to salmonid alphavirus subtype 3 experimental infections in atlantic salmon.salmonid alphavirus subtype-3 (sav-3) infection in atlantic salmon is exclusively found in norway. the salmonid alphaviruses have been well characterized at the genome level but there is limited information about the host-pathogen interaction phenomena. this study was undertaken to characterize the replication and spread of sav-3 in internal organs of experimentally infected atlantic salmon and the subsequent innate and adaptive immune responses. in addition, suitability of a cohabitation challe ...201223116479
the west nile virus capsid protein blocks apoptosis through a phosphatidylinositol 3-kinase-dependent mechanism.west nile virus (wnv) is a mosquito-transmitted pathogen that can cause serious disease in humans. our laboratories are focused on understanding how interactions between wnv proteins and host cells contribute to virus replication and pathogenesis. wnv replication is relatively slow, and on the basis of earlier studies, the virus appears to activate survival pathways that delay host cell death during virus replication. the wnv capsid is the first viral protein produced in infected cells; however, ...201223115297
gcn2 has inhibitory effect on human immunodeficiency virus-1 protein synthesis and is cleaved upon viral infection.the reversible phosphorylation of the alpha-subunit of eukaryotic translation initiation factor 2 (eif2alpha) is a well-characterized mechanism of translational control in response to a wide variety of cellular stresses, including viral infection. beside pkr, the eif2alpha kinase gcn2 participates in the cellular response against viral infection by rna viruses with central nervous system tropism. pkr has also been involved in the antiviral response against hiv-1, although this antiviral effect i ...201223110064
making connections in insect innate immunity. 201223100537
enterovirus 71 uses cell surface heparan sulfate glycosaminoglycan as an attachment receptor.enterovirus 71 (ev-71) infections are usually associated with mild hand, foot, and mouth disease in young children but have been reported to cause severe neurological complications with high mortality rates. to date, four ev-71 receptors have been identified, but inhibition of these receptors by antagonists did not completely abolish ev-71 infection, implying that there is an as yet undiscovered receptor(s). since ev-71 has a wide range of tissue tropisms, we hypothesize that ev-71 infections ma ...201223097443
transient activation of the pi3k-akt pathway by hepatitis c virus to enhance viral entry.the pi3k-akt signaling pathway plays an important role in cell growth and metabolism. here we report that hepatitis c virus (hcv) transiently activates the pi3k-akt pathway. this activation was observed as early as 15 min postinfection, peaked by 30 min, and became undetectable at 24 h postinfection. the activation of akt could also be mediated by uv-inactivated hcv, hcv pseudoparticle, and the ectodomain of the hcv e2 envelope protein. because antibodies directed against cd81 and claudin-1, but ...201223095753
autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation.autophagy is a cell biological pathway affecting immune responses. in vitro, autophagy acts as a cell-autonomous defense against mycobacterium tuberculosis, but its role in vivo is unknown. here we show that autophagy plays a dual role against tuberculosis: antibacterial and anti-inflammatory. m. tuberculosis infection of atg5(fl/fl) lysm-cre(+) mice relative to autophagy-proficient littermates resulted in increased bacillary burden and excessive pulmonary inflammation characterized by neutrophi ...201223093667
in vivo gene transfer targeting in pancreatic adenocarcinoma with cell surface antigens.pancreatic ductal adenocarcinoma is a deadly malignancy resistant to current therapies. it is critical to test new strategies, including tumor-targeted delivery of therapeutic agents. this study tested the possibility to target the transfer of a suicide gene in tumor cells using an oncotropic lentiviral vector.201223088623
sequestration of g3bp coupled with efficient translation inhibits stress granules in semliki forest virus infection.dynamic, mrna-containing stress granules (sgs) form in the cytoplasm of cells under environmental stresses, including viral infection. many viruses appear to employ mechanisms to disrupt the formation of sgs on their mrnas, suggesting that they represent a cellular defense against infection. here, we report that early in semliki forest virus infection, the c-terminal domain of the viral nonstructural protein 3 (nsp3) forms a complex with ras-gap sh3-domain-binding protein (g3bp) and sequesters i ...201223087212
transcriptional pausing controls a rapid antiviral innate immune response in drosophila.innate immune responses are characterized by precise gene expression whereby gene subsets are temporally induced to limit infection, although the mechanisms involved are incompletely understood. we show that antiviral immunity in drosophila requires the transcriptional pausing pathway, including negative elongation factor (nelf) that pauses rna polymerase ii (pol ii) and positive elongation factor b (p-tefb), which releases paused pol ii to produce full-length transcripts. we identify a set of g ...023084920
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