Publications

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zinc finger antiviral protein inhibits murine gammaherpesvirus 68 m2 expression and regulates viral latency in cultured cells.zinc finger antiviral protein (zap) is a host factor that specifically inhibits the replication of certain viruses by binding to specific viral mrnas and repressing mrna expression. here we report that zap inhibits expression of murine gammaherpesvirus 68 (mhv-68) m2, which plays important roles in establishment and maintenance of viral latency. downregulation of endogenous zap in cells harboring latent mhv-68 promoted lytic replication of the virus. these results suggest that zap inhibits m2 ex ...201222951821
autophagy as a stress-response and quality-control mechanism: implications for cell injury and human disease.autophagy, a vital catabolic process that degrades cytoplasmic components within the lysosome, is an essential cytoprotective response to pathologic stresses that occur during diseases such as cancer, ischemia, and infection. in addition to its role as a stress-response pathway, autophagy plays an essential quality-control function in the cell by promoting basal turnover of long-lived proteins and organelles, as well as by selectively degrading damaged cellular components. this homeostatic funct ...201223072311
making connections in insect innate immunity. 201223100537
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
expression of plasmid-based shrna against the e1 and nsp1 genes effectively silenced chikungunya virus replication.chikungunya virus (chikv) is a re-emerging alphavirus that causes chikungunya fever and persistent arthralgia in humans. currently, there is no effective vaccine or antiviral against chikv infection. therefore, this study evaluates whether rna interference which targets at viral genomic level may be a novel antiviral strategy to inhibit the medically important chikv infection.201223056297
vipr hmm: a hidden markov model for detecting recombination with microbial detection microarrays.current methods in diagnostic microbiology typically focus on the detection of a single genomic locus or protein in a candidate agent. the presence of the entire microbe is then inferred from this isolated result. problematically, the presence of recombination in microbial genomes would go undetected unless other genomic loci or protein components were specifically assayed. microarrays lend themselves well to the detection of multiple loci from a given microbe; furthermore, the inherent nature o ...201223044542
autophagy and selective deployment of atg proteins in antiviral defense.autophagy is an evolutionarily ancient process eukaryotic cells utilize to remove and recycle intracellular material in order to maintain cellular homeostasis. in metazoans, the autophagy machinery not only functions in this capacity but also has evolved to perform a diverse repertoire of intracellular transport and regulatory functions. in response to virus infections, the autophagy machinery degrades viruses, shuttles viral pathogen-associated molecular patterns to endosomes containing toll-li ...201223042773
testing of novel dengue virus 2 vaccines in african green monkeys: safety, immunogenicity, and efficacy.the immunogenicity and safety of three novel host-range vaccines containing deletions in the transmembrane domain of dengue virus serotype 2 (dv2) e glycoprotein were evaluated in african green monkeys. the shorter transmembrane domains are capable of functionally spanning an insect but not a mammalian cell membrane, resulting in production of viral mutants that have reduced infectivity in mammalian hosts but efficient growth in insect cells. groups of four monkeys received one dose each of test ...201222890035
living on the edge with too many mouths to feed: why dopamine neurons die.although genes, protein aggregates, environmental toxins, and other factors associated with parkinson's disease (pd) are widely distributed in the nervous system and affect many classes of neurons, a consistent feature of pd is the exceptional and selective vulnerability of dopamine (da) neurons of the snc. what is it about these neurons, among all other neurons in the brain, that makes them so susceptible in pd? we hypothesize that a major contributory factor is the unique cellular architecture ...201223008164
pathogenic characterization of a cervical lymph node derived from a patient with kawasaki disease.kawasaki disease (kd) is the most common cause of multisystem vasculitis in childhood. although cervical lymphadenitis is one of the major symptoms in kd, lymph node biopsy is rarely performed, because kd is usually diagnosed by clinical symptoms. a cervical lymph node biopsy was taken from a girl aged 1 year and 8 months who had suspected lymphoma, but she was diagnosed with kd after the biopsy. the cervical lymph node specimen was analyzed with multivirus real-time pcr that can detect >160 vir ...201223071864
rnase l triggers autophagy in response to viral infections.autophagy is a programmed homeostatic response to diverse types of cellular stress that disposes of long-lived proteins, organelles, and invading microbes within double-membraned structures called autophagosomes. the 2',5'-oligoadenylate/rnase l system is a virus-activated host rnase pathway that disposes of or processes viral and cellular single-stranded rnas. here we report that activation of rnase l during viral infections induces autophagy. accordingly, infections with encephalomyocarditis v ...201222875977
translational repression precedes and is required for zap-mediated mrna decay.translational repression and mrna degradation are two major mechanisms for post-transcriptional regulation of gene expression. the detailed relationship between these two processes is not yet well established. zinc-finger antiviral protein (zap) inhibits the replication of certain viruses, including human immunodeficiency virus 1, by binding directly to specific viral mrnas and recruiting cellular mrna degradation machinery to degrade the target mrna. here, we report that zap also inhibits the t ...201223023399
role of bunyamwera orthobunyavirus nss protein in infection of mosquito cells.bunyamwera orthobunyavirus is both the prototype and study model of the bunyaviridae family. the viral nss protein seems to contribute to the different outcomes of infection in mammalian and mosquito cell lines. however, only limited information is available on the growth of bunyamwera virus in cultured mosquito cells other than the aedes albopictus c6/36 line.201223029584
intrahepatic infiltrating nk and cd8 t cells cause liver cell death in different phases of dengue virus infection.elevated liver enzyme level is an outstanding feature in patients with dengue. however, the pathogenic mechanism of liver injury has not been clearly demonstrated. in this study, employing a mouse model we aimed to investigate the immunopathogenic mechanism of dengue liver injury. immunocompetent c57bl/6 mice were infected intravenously with dengue virus strain 16681. infected mice had transient viremia, detectable viral capsid gene and cleaved caspase 3 in the liver. in the mean time, nk cell a ...201223050007
replication of respiratory syncytial virus is inhibited by the host defense molecule viperin.respiratory syncytial virus (rsv) is an important viral pathogen of otitis media, bronchiolitis, and pneumonia. as infection of the upper airways is a precondition for the development of these diseases, understanding rsv pathogenesis and the host response induced by rsv in this niche may enable the development of novel therapeutic strategies against this virus. we have used a microarray approach and showed that expression of the gene that encodes the antiviral protein viperin was significantly u ...201223018837
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
west nile virus (wnv) replication is independent of autophagy in mammalian cells.autophagy is a homeostatic process responsible for recycling cytosolic proteins and organelles. moreover, this pathway contributes to the cell's intrinsic innate defenses. while many viruses have evolved mechanisms to antagonize the antiviral effects of the autophagy pathway, others subvert autophagy to facilitate replication. here, we have investigated the role of autophagy in west nile virus (wnv) replication. experiments in cell lines derived from a variety of sources, including the kidney, l ...201223029249
everybody wins! poland hosts thrilling competitions of viruses, rnai and football teams.the esf-embo conference on 'antiviral rnai: from molecular biology towards applications' took place in june 2012 in pultusk, poland. it brought together scientists working at the interface of rnai and virus infections in different organisms, covering the complete range from basic mechanisms of rna silencing to rnai-based antiviral therapy.201222986551
macrophage autophagy in immunity to cryptococcus neoformans and candida albicans.autophagy is used by eukaryotes in bulk cellular material recycling and in immunity to intracellular pathogens. we evaluated the role of macrophage autophagy in the response to cryptococcus neoformans and candida albicans, two important opportunistic fungal pathogens. the autophagosome marker lc3 (microtubule-associated protein 1 light chain 3 alpha) was present in most macrophage vacuoles containing c. albicans. in contrast, lc3 was found in only a few vacuoles containing c. neoformans previous ...201222710871
intracytoplasmic trapping of influenza virus by a lipophilic derivative of aglycoristocetin.we report on a new anti-influenza virus agent, sa-19, a lipophilic glycopeptide derivative consisting of aglycoristocetin coupled to a phenylbenzyl-substituted cyclobutenedione. in madin-darby canine kidney cells infected with influenza a/h1n1, a/h3n2, or b virus, sa-19 displayed a 50% antivirally effective concentration of 0.60 μm and a selectivity index (ratio of cytotoxic versus antiviral concentration) of 112. sa-19 was 11-fold more potent than unsubstituted aglycoristocetin and was active i ...201222740402
large ribosomal protein 4 increases efficiency of viral recoding sequences.expression of retroviral replication enzymes (pol) requires a controlled translational recoding event to bypass the stop codon at the end of gag. this recoding event occurs either by direct suppression of termination via the insertion of an amino acid at the stop codon (readthrough) or by alteration of the mrna reading frame (frameshift). here we report the effects of a host protein, large ribosomal protein 4 (rpl4), on the efficiency of recoding. using a dual luciferase reporter assay, we found ...201222718819
fighting mycobacteria through isgylation. 201222940737
comprehensive proteomic analysis of nonintegrin laminin receptor interacting proteins.human nonintegrin laminin receptor is a multifunctional protein acting as an integral component of the ribosome and a cell surface receptor for laminin-1. the laminin receptor is overexpressed in several human cancers and is also the cell surface receptor for several viruses and pathogenic prion proteins, making it a pathologically significant protein. this study focused on the proteomic characterization of laminin receptor interacting proteins from mus musculus. the use of affinity chromatograp ...201222909348
west nile virus growth is independent of autophagy activation.west nile virus (wnv) is an arthropod-borne virus with a worldwide distribution that causes neurologic disease and death. autophagy is a cellular homeostatic mechanism involved in antiviral responses but can be subverted to support viral growth as well. we show that autophagy is induced by wnv infection in cell culture and in primary neuron cultures. following wnv infection, lysosomes co-localize with autophagosomes resulting in lc3b-ii turnover and autolysosomal acidification. however, activati ...201222939285
heterozygous tbk1 mutations impair tlr3 immunity and underlie herpes simplex encephalitis of childhood.childhood herpes simplex virus-1 (hsv-1) encephalitis (hse) may result from single-gene inborn errors of tlr3 immunity. tlr3-dependent induction of ifn-α/β or ifn-λ is crucial for protective immunity against primary hsv-1 infection in the central nervous system (cns). we describe here two unrelated children with hse carrying different heterozygous mutations (d50a and g159a) in tbk1, the gene encoding tank-binding kinase 1, a kinase at the crossroads of multiple ifn-inducing signaling pathways. b ...201222851595
hepatitis c virus translation preferentially depends on active rna replication.hepatitis c virus (hcv) rna initiates its replication on a detergent-resistant membrane structure derived from the endoplasmic reticulum (er) in the hcv replicon cells. by performing a pulse-chase study of bru-labeled hcv rna, we found that the newly-synthesized hcv rna traveled along the anterograde-membrane traffic and moved away from the er. presumably, the rna moved to the site of translation or virion assembly in the later steps of viral life cycle. in this study, we further addressed how h ...201222937067
translational regulation of anopheles gambiae mrnas in the midgut during plasmodium falciparum infection.malaria is caused by plasmodium parasites, which are transmitted via the bites of infected anopheline mosquitoes. midgut invasion is a major bottleneck for plasmodium development inside the mosquito vectors. malaria parasites in the midgut are surrounded by a hostile environment rich in digestive enzymes, while a rapidly responding immune system recognizes plasmodium ookinetes and recruits killing factors from the midgut and surrounding tissues, dramatically reducing the population of invading o ...201222857387
retinoblastoma protein induction by hiv viremia or ccr5 in monocytes exposed to hiv-1 mediates protection from activation-induced apoptosis: ex vivo and in vitro study.we have previously described an antiapoptotic steady-state gene expression profile in circulating human monocytes from asymptomatic viremic hiv(+) donors, but the mechanism associated with this apoptosis resistance remains to be fully elucidated. here, we show that rb1 activation is a dominant feature of apoptosis resistance in monocytes exposed to hiv-1 in vivo (as measured ex vivo) and in vitro. monocytes from asymptomatic viremic hiv(+) individuals show a positive correlation between levels o ...201222701041
identification of a novel antiviral inhibitor of the flavivirus guanylyltransferase enzyme.arthropod-borne flavivirus infection causes serious morbidity and mortality worldwide, but there are currently no effective antiflaviviral chemotherapeutics available for human use. therefore, it is critical that new therapeutics against virus-specific targets be developed. to identify new compounds that may be used as broadly active flavivirus therapeutics, we have performed a high-throughput screening of 235,456 commercially available compounds for small-molecule inhibitors of the dengue virus ...201222674988
identification of novel host cell binding partners of oas1b, the protein conferring resistance to flavivirus-induced disease in mice.oas1b was previously identified as the product of the flv(r) allele that confers flavivirus-specific resistance to virus-induced disease in mice by an uncharacterized, rnase l-independent mechanism. to gain insights about the mechanism by which oas1b specifically reduces the efficiency of flavivirus replication, cellular protein interaction partners were identified and their involvement in the oas1b-mediated flavivirus resistance mechanism was analyzed. initial difficulties in getting the two-hy ...201222623793
a single mutation in the glycophorin a binding site of hepatitis a virus enhances virus clearance from the blood and results in a lower fitness variant.hepatitis a virus (hav) has previously been reported to bind to human red blood cells through interaction with glycophorin a. residue k221 of vp1 and the surrounding vp3 residues are involved in such an interaction. this capsid region is specifically recognized by the monoclonal antibody h7c27. a monoclonal antibody-resistant mutant with the mutation g1217d has been isolated. in the present study, the g1217d mutant was characterized physically and biologically in comparison with the parental hm1 ...201222593170
tracking expression and subcellular localization of rna and protein species using high-throughput single cell imaging flow cytometry.we report a high-throughput application of multispectral imaging flow cytometry (mifc) for analyzing the expression and localization of both rna and protein molecules in a heterogeneous population of cells. the approach was developed using polyadenylated nuclear (pan) rna, an abundant, noncoding rna expressed by kaposi's sarcoma-associated herpesvirus (kshv) during the lytic phase of infection. high levels of pan rna are, in part, dependent on its interaction with poly(a)-binding protein c1 (pab ...201222745225
a graph theory method for determination of cryo-em image focuses.accurate determination of micrograph focuses is essential for averaging multiple images to reach high-resolution 3-d reconstructions in electron cryo-microscopy (cryo-em). current methods use iterative fitting of focus-dependent simulated power spectra to the power spectra of experimental images, with the fitting performed independently for different images. here we have developed a novel graph theory based method in which the rotational average focus and individual angular sector focuses of all ...201222842112
matching biochemical and functional efficacies confirm zip as a potent competitive inhibitor of pkmζ in neurons.pkmζ is an autonomously active, atypical protein kinase c (apkc) isoform that is both necessary and sufficient for maintaining long-term potentiation (ltp) and long-term memory. the myristoylated ζ-pseudosubstrate peptide, zip, potently inhibits pkmζ biochemically in vitro, within cultured cells, and within neurons in hippocampal slices, and reverses ltp maintenance and erases long-term memory storage. a recent study (wu-zhang et al., 2012), however, suggested zip was not effective on a pkmζ fus ...201222846225
a novel coding-region rna element modulates infectious dengue virus particle production in both mammalian and mosquito cells and regulates viral replication in aedes aegypti mosquitoes.dengue virus (denv) is an enveloped flavivirus with a positive-sense rna genome transmitted by aedes mosquitoes, causing the most important arthropod-borne viral disease affecting humans. relatively few cis-acting rna regulatory elements have been described in the denv coding-region. here, by introducing silent mutations into a denv-2 infectious clone, we identify the conserved capsid-coding region 1 (ccr1), an rna sequence element that regulates viral replication in mammalian cells and to a gre ...201222840606
interaction of endogenous tau protein with synaptic proteins is regulated by n-methyl-d-aspartate receptor-dependent tau phosphorylation.amyloid-β and tau protein are the two most prominent factors in the pathology of alzheimer disease. recent studies indicate that phosphorylated tau might affect synaptic function. we now show that endogenous tau is found at postsynaptic sites where it interacts with the psd95-nmda receptor complex. nmda receptor activation leads to a selective phosphorylation of specific sites in tau, regulating the interaction of tau with fyn and the psd95-nmda receptor complex. based on our results, we propose ...201222833681
neurogranin targets calmodulin and lowers the threshold for the induction of long-term potentiation.calcium entry and the subsequent activation of camkii trigger synaptic plasticity in many brain regions. the induction of long-term potentiation (ltp) in the ca1 region of the hippocampus requires a relatively high amount of calcium-calmodulin. this requirement is usually explained, based on in vitro and theoretical studies, by the low affinity of camkii for calmodulin. an untested hypothesis, however, is that calmodulin is not randomly distributed within the spine and its targeting within the s ...201222848456
targeted gene transfer of different genes to presynaptic and postsynaptic neocortical neurons connected by a glutamatergic synapse.genetic approaches to analyzing neuronal circuits and learning would benefit from a technology to first deliver a specific gene into presynaptic neurons, and then deliver a different gene into an identified subset of their postsynaptic neurons, connected by a specific synapse type. here, we describe targeted gene transfer across a neocortical glutamatergic synapse, using as the model the projection from rat postrhinal to perirhinal cortex. the first gene transfer, into the presynaptic neurons in ...201222820303
loss of stress response as a consequence of viral infection: implications for disease and therapy.herein, we propose that viral infection can induce a deficient cell stress response and thereby impairs stress tolerance and makes tissues vulnerable to damage. having a valid paradigm to address the pathological impacts of viral infections could lead to effective new therapies for diseases that have previously been unresponsive to intervention. host response to viral infections can also lead to autoimmune diseases like type 1 diabetes. in the case of newcastle disease virus, the effects of vira ...201222797944
identifying host factors that regulate viral infection. 201222807672
regulation of the autophagic bcl-2/beclin 1 interaction.autophagy is an intracellular degradation process responsible for the delivery of cellular material to the lysosomes. one of the key mechanisms for control of autophagy is the modulation of the interaction between the autophagic protein beclin 1 and the members of the anti-apoptotic bcl-2 family (e.g., bcl-2, bcl-xl and mcl-1). this binding is regulated by a variety of proteins and compounds that are able to enhance or inhibit the bcl-2/beclin 1 interaction in order to repress or activate autoph ...201224710477
antiviral activity of a small molecule deubiquitinase inhibitor occurs via induction of the unfolded protein response.ubiquitin (ub) is a vital regulatory component in various cellular processes, including cellular responses to viral infection. as obligate intracellular pathogens, viruses have the capacity to manipulate the ubiquitin (ub) cycle to their advantage by encoding ub-modifying proteins including deubiquitinases (dubs). however, how cellular dubs modulate specific viral infections, such as norovirus, is poorly understood. to examine the role of dubs during norovirus infection, we used wp1130, a small ...201222792064
extended jak activation and delayed stat1 dephosphorylation contribute to the distinct signaling profile of cns neurons exposed to interferon-gamma.although interferon-gamma (ifn-γ) plays a critical role in the noncytolytic elimination of many neurotropic viral infections, the signaling response to this cytokine has not been extensively characterized in primary cns neurons. we previously demonstrated that the ifn-γ response at the signaling and gene expression levels is temporally extended in primary mouse hippocampal neurons, as compared to the transient response of primary mouse embryonic fibroblasts (mef). we hypothesize that the protrac ...201222769061
autophagy and immunity - insights from human herpesviruses.the herpesviruses are a family of double-stranded dna viruses that infect a wide variety of organisms. having co-evolved with their hosts over millennia, herpesviruses have developed a large repertoire of mechanisms to manipulate normal cellular processes for their own benefit. consequently, studies on these viruses have made important contributions to our understanding of fundamental biological processes. here we describe recent research on the human herpesviruses that has contributed to our un ...201222783253
engineered hepatitis b virus surface antigen l protein particles for in vivo active targeting of splenic dendritic cells.dendritic cells (dcs) are key regulators of adaptive t-cell responses. by capturing exogenous antigens and presenting antigen-derived peptides via major histocompatibility complex molecules to naïve t cells, dcs induce antigen-specific immune responses in vivo. in order to induce effective host immune responses, active delivery of exogenous antigens to dcs is considered important for future vaccine development. we recently generated bionanocapsules (bncs) consisting of hepatitis b virus surface ...201222848163
structure of the surface layer of the methanogenic archaean methanosarcina acetivorans.archaea have a self-assembling proteinaceous surface (s-) layer as the primary and outermost boundary of their cell envelopes. the s-layer maintains structural rigidity, protects the organism from adverse environmental elements, and yet provides access to all essential nutrients. we have determined the crystal structure of one of the two "homologous" tandem polypeptide repeats that comprise the methanosarcina acetivorans s-layer protein and propose a high-resolution model for a microbial s-layer ...201222753492
overexpression of membrane proteins in mammalian cells for structural studies.the number of structures of integral membrane proteins from higher eukaryotes is steadily increasing due to a number of innovative protein engineering and crystallization strategies devised over the last few years. however, it is sobering to reflect that these structures represent only a tiny proportion of the total number of membrane proteins encoded by a mammalian genome. in addition, the structures determined to date are of the most tractable membrane proteins, i.e., those that are expressed ...201222963530
effects of larval rearing temperature on immature development and west nile virus vector competence of culex tarsalis.temperature is known to induce changes in mosquito physiology, development, ecology, and in some species, vector competence for arboviruses. since colonized mosquitoes are reared under laboratory conditions that can be significantly different from their field counterparts, laboratory vector competence experiments may not accurately reflect natural vector-virus interactions.201222967798
preparation of bioactive interferon alpha-loaded polysaccharide nanoparticles using a new approach of temperature-induced water phase/water-phase emulsion.the aim of this study was to develop a temperature-induced polyethylene glycol (peg) water phase/polysaccharide water-phase emulsion approach for preparing interferon alpha-2b (ifnα-2b)-loaded polysaccharide nanoparticles. ifnα-2b was first added to a mixture of an aqueous solution of peg and polysaccharide. the mixture solution was stirred in a magnetic stirrer at a rate of 2000 rpm for 45 seconds at 0°c ± 0.5°c. the solution was then prefrozen at different temperatures. the polysaccharide and ...201222973103
nlrs, inflammasomes, and viral infection.nlr proteins are innate immune sensors that respond to microbial infection. upon pathogen infection, some nlr proteins form large complexes, called inflammasomes, which activate caspase-1 and induce the production of active il-1β and il-18. activation of inflammasomes can also lead to an inflammatory cell death program, named pyroptosis. in this review, we will discuss the role of various nlr proteins in sensing different viral infections, as well as the strategies used by several rna and dna vi ...201222581934
activity based protein profiling to detect serine hydrolase alterations in virus infected cells.activity-based protein profiling (abpp) is a newly emerging technique that uses active site-directed probes to monitor the functional status of enzymes. serine hydrolases are one of the largest families of enzymes in mammals. more than 200 serine hydrolases have been identified, but little is known about their specific roles. serine hydrolases are involved in a variety of physiological functions, including digestion, immune response, blood coagulation, and reproduction. abpp has been used recent ...201223024641
dengue reporter viruses reveal viral dynamics in interferon receptor-deficient mice and sensitivity to interferon effectors in vitro.dengue virus (denv) is a global disease threat for which there are no approved antivirals or vaccines. establishing state-of-the-art screening systems that rely on fluorescent or luminescent reporters may accelerate the development of anti-denv therapeutics. however, relatively few reporter denv platforms exist. here, we show that denv can be genetically engineered to express a green fluorescent protein or firefly luciferase. reporter viruses are infectious in vitro and in vivo and are sensitive ...201222908290
evidence for a genetic and physical interaction between nonstructural proteins ns1 and ns4b that modulates replication of west nile virus.flavivirus ns1 is a nonstructural glycoprotein that is expressed on the cell surface and secreted into the extracellular space. despite its transit through the secretory pathway, ns1 is an essential gene linked to early viral rna replication. how this occurs has remained a mystery given the disparate localization of ns1 and the viral rna replication complex, as the latter is present on the cytosolic face of the endoplasmic reticulum (er). we recently identified an n-terminal di-amino acid motif ...201222553322
autophagic clearance of sin nombre hantavirus glycoprotein gn promotes virus replication in cells.hantavirus glycoprotein precursor (gpc) is posttranslationally cleaved into two glycoproteins, gn and gc. cells transfected with plasmids expressing either gpc or both gn and gc revealed that gn is posttranslationally degraded. treatment of cells with the autophagy inhibitors 3-methyladenine, ly-294002, or wortmanin rescued gn degradation, suggesting that gn is degraded by the host autophagy machinery. confocal microscopic imaging showed that gn is targeted to autophagosomes for degradation by a ...201222553339
how do viruses interact with stress-associated rna granules? 201222761570
overexpression of serum response factor in astrocytes improves neuronal plasticity in a model of early alcohol exposure.neuronal plasticity deficits underlie many of the cognitive problems seen in fetal alcohol spectrum disorders (fasd). we have developed a ferret model showing that early alcohol exposure leads to a persistent disruption in ocular dominance (od) plasticity. recently, we showed that this deficit could be reversed by overexpression of serum response factor (srf) in the primary visual cortex during the period of monocular deprivation (md). surprisingly, this restoration was observed throughout the e ...201222742904
viral flice inhibitory protein of rhesus monkey rhadinovirus inhibits apoptosis by enhancing autophagosome formation.rhesus monkey rhadinovirus (rrv) is a gamma-2 herpesvirus closely related to human herpesvirus 8 (hhv8). rrv encodes viral flice inhibitory protein (vflip), which has death effector domains. little is known about rrv vflip. this study intended to examine its function in apoptosis. here we found that rrv vflip inhibits apoptosis induced by tumor necrosis factor-α (tnf-α) and cycloheximide. in hela cells with vflip expression, the cleavage of poly [adp-ribose] polymerase 1 (parp-1) and activities ...201222745754
disrupted cortical function underlies behavior dysfunction due to social isolation.stressful events during early childhood can have a profound lifelong influence on emotional and cognitive behaviors. however, the mechanisms by which stress affects neonatal brain circuit formation are poorly understood. here, we show that neonatal social isolation disrupts molecular, cellular, and circuit developmental processes, leading to behavioral dysfunction. neonatal isolation prevented long-term potentiation and experience-dependent synaptic trafficking of α-amino-3-hydroxy-5-methylisoxa ...201222706303
variability in detection and quantification of interferon β-1b-induced neutralizing antibodies.interferon-beta (ifnb) therapy for multiple sclerosis can lead to the induction of neutralizing antibodies (nabs) against ifnb. various methods are used for detection and quantification of nabs.201222703536
θ-defensins: cyclic peptides with endless potential.θ-defensins, the only cyclic peptides of animal origin, have been isolated from the leukocytes of rhesus macaques and baboons. their biogenesis is unusual because each peptide is an 18-residue chimera formed by the head-to-tail splicing of nonapeptides derived from two separate precursors. θ-defensins have multiple arginines and a ladder-like tridisulfide array spanning their two antiparallel β-strands. human θ-defensin genes contain a premature stop codon that prevents effective translation of ...201222700960
multiple approaches to investigate the transport and activity-dependent release of bdnf and their application in neurogenetic disorders.studies utilizing genetic and pharmacological manipulations in rodent models and neuronal cultures have revealed myriad roles of brain-derived neurotrophic factor (bdnf). currently, this knowledge of bdnf function is being translated into improvement strategies for several debilitating neurological disorders in which bdnf abnormalities play a prominent role. common among the bdnf-related disorders are irregular trafficking and release of mature bdnf (mbdnf) and/or its prodomain predecessor, prob ...201222720171
covalent protein modification with isg15 via a conserved cysteine in the hinge region.the ubiquitin-like protein isg15 (interferon-stimulated gene of 15 kda) is strongly induced by type i interferons and displays antiviral activity. as other ubiquitin-like proteins (ubls), isg15 is post-translationally conjugated to substrate proteins by an isopeptide bond between the c-terminal glycine of isg15 and the side chains of lysine residues in the substrates (isgylation). isg15 consists of two ubiquitin-like domains that are separated by a hinge region. in many orthologs, this region co ...201222693631
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
rna interference as a cellular defense mechanism against the dna virus baculovirus.in insects, the rna interference (rnai) pathway plays a major role in antiviral responses, as shown against many rna viruses. the response includes the cleavage of double-stranded rna genome or intermediates, produced during replication, into viral short interfering rnas (v-sirnas). using deep sequencing, we found that a large number of small reads of ∼20 nucleotides from helicoverpa armigera larvae infected with helicoverpa armigera single nucleopolyhedrovirus (hasnpv) were mapped to certain op ...201223055564
gamma interferon (ifn-γ) receptor restricts systemic dengue virus replication and prevents paralysis in ifn-α/β receptor-deficient mice.we previously reported that mice lacking alpha/beta and gamma interferon receptors (ifn-α/βr and -γr) uniformly exhibit paralysis following infection with the dengue virus (denv) clinical isolate pl046, while only a subset of mice lacking the ifn-γr alone and virtually no mice lacking the ifn-α/βr alone develop paralysis. here, using a mouse-passaged variant of pl046, strain s221, we show that in the absence of the ifn-α/βr, signaling through the ifn-γr confers approximately 140-fold greater res ...201222973027
longitudinal analysis of the human antibody response to chikungunya virus infection: implications for serodiagnosis and vaccine development.chikungunya virus (chikv) is an alphavirus which causes chronic and incapacitating arthralgia in humans. although previous studies have shown that antibodies against the virus are produced during and after infection, the fine specificity of the antibody response against chikv is not known. here, using plasma from patients at different times postinfection, we characterized the antibody response against various proteins of the virus. we have shown that the e2 and e3 glycoproteins and the capsid an ...201223015702
foot-and-mouth disease virus induces autophagosomes during cell entry via a class iii phosphatidylinositol 3-kinase-independent pathway.autophagy is an intracellular pathway that can contribute to innate antiviral immunity by delivering viruses to lysosomes for degradation or can be beneficial for viruses by providing specialized membranes for virus replication. here, we show that the picornavirus foot-and-mouth disease virus (fmdv) induces the formation of autophagosomes. induction was dependent on atg5, involved processing of lc3 to lc3ii, and led to a redistribution of lc3 from the cytosol to punctate vesicles indicative of a ...201222993157
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
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
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
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
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
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
induction of stress granule-like structures in vesicular stomatitis virus-infected cells.previous studies from our laboratory revealed that cellular poly(c) binding protein 2 (pcbp2) downregulates vesicular stomatitis virus (vsv) gene expression. we show here that vsv infection induces the formation of granular structures in the cytoplasm containing cellular rna-binding proteins, including pcbp2, t-cell-restricted intracellular antigen 1 (tia1), and tia1-related protein (tiar). depletion of tia1 via small interfering rnas (sirnas), but not depletion of tiar, results in enhanced vsv ...201223077311
long-distance rna-rna interactions in the coronavirus genome form high-order structures promoting discontinuous rna synthesis during transcription.coronavirus (cov) transcription requires a high-frequency recombination process that links newly synthesized minus-strand subgenomic rna copies to the leader region, which is present only once, at the 5' end of the genome. this discontinuous rna synthesis step is based on the complementarity between the transcription-regulating sequences (trss) at the leader region and those preceding each gene in the nascent minus-strand rna. furthermore, the template switch requires the physical proximity of r ...201223055566
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
tailored hiv-1 vectors for genetic modification of primary human dendritic cells and monocytes.monocyte-derived dendritic cells (mddcs) play a key role in the regulation of the immune system and are the target of numerous gene therapy applications. the genetic modification of mddcs is possible with human immunodeficiency virus type 1 (hiv-1)-derived lentiviral vectors (lvs) but requires high viral doses to bypass their natural resistance to viral infection, and this in turn affects their physiological properties. to date, a single viral protein is able to counter this restrictive phenotyp ...201223077304
a novel inhibitor of dengue virus replication that targets the capsid protein.dengue viruses (denv) infect 50 to 100 million people worldwide per year, of which 500,000 develop severe life-threatening disease. this mosquito-borne illness is endemic in most tropical and subtropical countries and has spread significantly over the last decade. while there are several promising vaccine candidates in clinical trials, there are currently no approved vaccines or therapeutics available for treatment of dengue infection. here, we describe a novel small-molecule compound, st-148, t ...201223070172
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
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
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
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
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
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
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
proteomics-based methods for discovery, quantification, and validation of protein-protein interactions. 201223157382
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
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
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
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
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
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
the alphavirus e3 glycoprotein functions in a clade-specific manner.the 80 trimeric, glycoprotein spikes that cover the surface of alphavirus particles are required for mediating viral entry into a host cell. spike assembly is a regulated process that requires interactions between five structural proteins, e3, e2, 6k and its translational frameshift product tf, and e1. e3 is a small, ∼65-amino-acid glycoprotein that has two known functions: e3 serves as the signal sequence for translocation of the e3-e2-6k-e1 polyprotein into the endoplasmic reticulum (er), and ...201223035234
dephosphorylation of hur protein during alphavirus infection is associated with hur relocalization to the cytoplasm.we have demonstrated previously that the cellular hur protein binds u-rich elements in the 3' untranslated region (utr) of sindbis virus rna and relocalizes from the nucleus to the cytoplasm upon sindbis virus infection in 293t cells. in this study, we show that two alphaviruses, ross river virus and chikungunya virus, lack the conserved high-affinity u-rich hur binding element in their 3' utrs but still maintain the ability to interact with hur with nanomolar affinities through alternative bind ...201222915590
isolation and characterisation of a human-like antibody fragment (scfv) that inactivates veev in vitro and in vivo.venezuelan equine encephalitis virus (veev) belongs to the alphavirus genus and several species of this family are pathogenic to humans. the viruses are classified as potential agents of biological warfare and terrorism and sensitive detection as well as effective prophylaxis and antiviral therapies are required.in this work, we describe the isolation of the anti-veev single chain fragment variable (scfv), tor67-3b4, from a non-human primate (nhp) antibody gene library. we report its recloning i ...201222666347
alphaviruses: population genetics and determinants of emergence.alphaviruses are responsible for several medically important emerging diseases and are also significant veterinary pathogens. due to the aerosol infectivity of some alphaviruses and their ability to cause severe, sometimes fatal neurologic diseases, they are also of biodefense importance. this review discusses the ecology, epidemiology and molecular virology of the alphaviruses, then focuses on three of the most important members of the genus: venezuelan and eastern equine encephalitis and chiku ...201222522323
proteomic analysis of chikungunya virus infected microgial cells.chikungunya virus (chikv) is a recently re-emerged public health problem in many countries bordering the indian ocean and elsewhere. chikungunya fever is a relatively self limiting febrile disease, but the consequences of chikungunya fever can include a long lasting, debilitating arthralgia, and occasional neurological involvement has been reported. macrophages have been implicated as an important cell target of chikv with regards to both their role as an immune mediator, as well evidence pointi ...201222514668
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