Publications

TitleAbstractYear
Filter
PMID(sorted ascending)
Filter
histone h3 lysine 9 di-methylation as an epigenetic signature of the interferon response.effective antiviral immunity depends on the ability of infected cells or cells triggered with virus-derived nucleic acids to produce type i interferon (ifn), which activates transcription of numerous antiviral genes. however, disproportionately strong or chronic ifn expression is a common cause of inflammatory and autoimmune diseases. we describe an epigenetic mechanism that determines cell type-specific differences in ifn and ifn-stimulated gene (isg) expression in response to exogenous signals ...201222412156
transmission dynamics of an insect-specific flavivirus in a naturally infected culex pipiens laboratory colony and effects of co-infection on vector competence for west nile virus.we established a laboratory colony of culex pipiens mosquitoes from eggs collected in colorado and discovered that mosquitoes in the colony are naturally infected with culex flavivirus (cxfv), an insect-specific flavivirus. in this study we examined transmission dynamics of cxfv and effects of persistent cxfv infection on vector competence for west nile virus (wnv). we found that vertical transmission is the primary mechanism for persistence of cxfv in cx. pipiens, with venereal transmission pot ...201222425062
rapid, specific detection of alphaviruses from tissue cultures using a replicon-defective reporter gene assay.we established a rapid, specific technique for detecting alphaviruses using a replicon-defective reporter gene assay derived from the sindbis virus xj-160. the pvaxj expression vector containing the xj-160 genome was engineered to form the expression vectors pvaxj-egfp expressing enhanced green fluorescence protein (egfp) or pvaxj-gluc expressing gaussia luciferase (gluc). the replicon-defective reporter plasmids pvaxj-egfpδnsp4 and pvaxj-glucδnsp4 were constructed by deleting 1139 bp in the non ...201222427930
anopheles gambiae antiviral immune response to systemic o'nyong-nyong infection.mosquito-borne viral diseases cause significant burden in much of the developing world. although host-virus interactions have been studied extensively in the vertebrate host, little is known about mosquito responses to viral infection. in contrast to mosquitoes of the aedes and culex genera, anopheles gambiae, the principal vector of human malaria, naturally transmits very few arboviruses, the most important of which is o'nyong-nyong virus (onnv). here we have investigated the a. gambiae immune ...201222428080
novel inhibitors of neurotropic alphavirus replication that improve host survival in a mouse model of acute viral encephalitis.arboviral encephalitis is a potentially devastating human disease with no approved therapies that target virus replication. we previously discovered a novel class of thieno[3,2-b]pyrrole-based inhibitors active against neurotropic alphaviruses such as western equine encephalitis virus (weev) in cultured cells. in this report, we describe initial development of these novel antiviral compounds, including bioisosteric replacement of the 4h-thieno[3,2-b]pyrrole core with indole to improve metabolic ...201222428985
the role of bcl-2 family proteins in therapy responses of malignant astrocytic gliomas: bcl2l12 and beyond.glioblastoma (gbm) is a highly aggressive and lethal brain cancer with a median survival of less than two years after diagnosis. hallmarks of gbm tumors include soaring proliferative indices, high levels of angiogenesis, diffuse invasion into normal brain parenchyma, resistance toward therapy-induced apoptosis, and pseudopallisading necrosis. despite the recent advances in neurosurgery, radiation therapy, and the development of targeted chemotherapeutic regimes, gbm remains one of the deadliest ...201222431925
interferon-β sensitivity of tumor cells correlates with poor response to va7 virotherapy in mouse glioma models.in our recent study, replicative alphaviral vector va7 was found to be effective against orthotopic human u87-glioma xenografts in an athymic mouse model eradicating the tumors with single intravenous (i.v.) injection. here, we tested the efficacy of va7 in immunocompetent orthotopic gl261 and ct-2a glioma models of c57bl/6 mouse in vivo. the cell lines were susceptible to va7 infection in vitro, but gl261 infection was highly restricted in confluent cell cultures, and mouse interferon-β (ifnβ) ...201222434140
accumulation of autophagosomes in semliki forest virus-infected cells is dependent on expression of the viral glycoproteins.autophagy is a cellular process that sequesters cargo in double-membraned vesicles termed autophagosomes and delivers this cargo to lysosomes to be degraded. it is enhanced during nutrient starvation to increase the rate of amino acid turnover. diverse roles for autophagy have been reported for viral infections, including the assembly of viral replication complexes on autophagic membranes and protection of host cells from cell death. here, we show that autophagosomes accumulate in semliki forest ...201222438538
effects of manipulating apoptosis on sindbis virus infection of aedes aegypti mosquitoes.improved control of vector-borne diseases requires an understanding of the molecular factors that determine vector competence. apoptosis has been shown to play a role in defense against viruses in insects and mammals. although some observations suggest a correlation between apoptosis and resistance to arboviruses in mosquitoes, there is no direct evidence tying apoptosis to arbovirus vector competence. to determine whether apoptosis can influence arbovirus replication in mosquitoes, we manipulat ...201222438551
clonal propagation of phyllanthus amarus: a hepatoprotector.the micropropagation protocol for phyllanthus amarus, an important medicinal herb used widely for the treatment of hepatitis in ethnomedicinal systems, was standardized with shoot tip and single node explants.022438668
a proteome map of primary cultured rat schwann cells.schwann cells (scs) are the principal glial cells of the peripheral nervous system with a wide range of biological functions. scs play a key role in peripheral nerve regeneration and are involved in several hereditary peripheral neuropathies. the objective of this study was to gain new insight into the whole protein composition of scs.201222443529
attenuation of chikungunya virus vaccine strain 181/clone 25 is determined by two amino acid substitutions in the e2 envelope glycoprotein.chikungunya virus (chikv) is the mosquito-borne alphavirus that is the etiologic agent of massive outbreaks of arthralgic febrile illness that recently affected millions of people in africa and asia. the only chikv vaccine that has been tested in humans, strain 181/clone 25, is a live-attenuated derivative of southeast asian human isolate strain af15561. the vaccine was immunogenic in phase i and ii clinical trials; however, it induced transient arthralgia in 8% of the vaccinees. there are five ...201222457519
dengue virus infection perturbs lipid homeostasis in infected mosquito cells.dengue virus causes ∼50-100 million infections per year and thus is considered one of the most aggressive arthropod-borne human pathogen worldwide. during its replication, dengue virus induces dramatic alterations in the intracellular membranes of infected cells. this phenomenon is observed both in human and vector-derived cells. using high-resolution mass spectrometry of mosquito cells, we show that this membrane remodeling is directly linked to a unique lipid repertoire induced by dengue virus ...201222457619
mannose binding lectin is required for alphavirus-induced arthritis/myositis.mosquito-borne alphaviruses such as chikungunya virus and ross river virus (rrv) are emerging pathogens capable of causing large-scale epidemics of virus-induced arthritis and myositis. the pathology of rrv-induced disease in both humans and mice is associated with induction of the host inflammatory response within the muscle and joints, and prior studies have demonstrated that the host complement system contributes to development of disease. in this study, we have used a mouse model of rrv-indu ...201222457620
sindbis virus induces the production of a novel class of endogenous sirnas in aedes aegypti mosquitoes.small rna regulatory pathways are used to control the activity of transposons, regulate gene expression and resist infecting viruses. we examined the biogenesis of mrna-derived endogenous short-interfering rnas (endo-sirnas) in the disease vector mosquito aedes aegypti. under standard conditions, mrna-derived endo-sirnas were produced from the bidirectional transcription of tail-tail overlapping gene pairs. upon infection with the alphavirus, sindbis virus (sinv), another class of mrna-derived e ...201222458920
ecological approaches to informing public health policy and risk assessments on emerging vector-borne zoonoses.pathogens associated with vector-borne zoonoses occur in enzootic cycles within nature. they are driven by a combination of vertebrate host and invertebrate vector population dynamics, which in turn respond to changes in environmental stimuli. human involvement in these cycles, and hence the occurrence of human disease, is often to act as incidental host. from a public health perspective our ability to better predict human outbreaks of these diseases and prepare intervention and mitigation strat ...201022460391
two-photon scanning microscopy of in vivo sensory responses of cortical neurons genetically encoded with a fluorescent voltage sensor in rat.a fluorescent voltage sensor protein "flare" was created from a kv1.4 potassium channel with yfp situated to report voltage-induced conformational changes in vivo. the rna virus sindbis introduced flare into neurons in the binocular region of visual cortex in rat. injection sites were selected based on intrinsic optical imaging. expression of flare occurred in the cell bodies and dendritic processes. neurons imaged in vivo using two-photon scanning microscopy typically revealed the soma best, di ...201222461770
neuromuscular manifestations of west nile virus infection.the most common neuromuscular manifestation of west nile virus (wnv) infection is a poliomyelitis syndrome with asymmetric paralysis variably involving one (monoparesis) to four limbs (quadriparesis), with or without brainstem involvement and respiratory failure. this syndrome of acute flaccid paralysis may occur without overt fever or meningoencephalitis. although involvement of anterior horn cells in the spinal cord and motor neurons in the brainstem are the major sites of pathology responsibl ...201222461779
virus recognition by toll-7 activates antiviral autophagy in drosophila.innate immunity is highly conserved and relies on pattern recognition receptors (prrs) such as toll-like receptors (identified through their homology to drosophila toll) for pathogen recognition. although drosophila toll is vital for immune recognition and defense, roles for the other eight drosophila tolls in immunity have remained elusive. here we have shown that toll-7 is a prr both in vitro and in adult flies; loss of toll-7 led to increased vesicular stomatitis virus (vsv) replication and m ...201222464169
synthesis and biological evaluation of a series of thieno-expanded tricyclic purine 2'-deoxy nucleoside analogues.introducing structural diversity into the nucleoside scaffold for use as potential chemotherapeutics has long been considered an important approach to drug design. in that regard, we have designed and synthesized a number of innovative 2'-deoxy expanded nucleosides where a heteroaromatic thiophene spacer ring has been inserted in between the imidazole and pyrimidine ring systems of the natural purine scaffold. the synthetic efforts towards realizing the expanded 2'-deoxy-guanosine and -adenosine ...201222464686
the immunology of neurodegeneration.while immune responses in neurodegeneration were regarded as little more than a curiosity a decade ago, they are now increasingly moving toward center stage. factors driving this movement include the recognition that most of the relevant immune molecules are produced within the brain, that microglia are proficient immune cells shaping neuronal circuitry and fate, and that systemic immune responses affect brain function. we will review this complex field from the perspective of neurons, extra-neu ...201222466657
the adaptive immune system in diseases of the central nervous system.tissues of the cns, such as the brain, optic nerves, and spinal cord, may be affected by a range of insults including genetic, autoimmune, infectious, or neurodegenerative diseases and cancer. the immune system is involved in the pathogenesis of many of these, either by causing tissue damage or alternatively by responding to disease and contributing to repair. it is clearly vital that cells of the immune system patrol the cns and protect against infection. however, in contrast to other tissues, ...201222466659
mayaro virus infection in traveler returning from amazon basin, northern peru. 201222469145
complexity of the microglial activation pathways that drive innate host responses during lethal alphavirus encephalitis in mice.microglia express multiple tlrs (toll-like receptors) and provide important host defence against viruses that invade the cns (central nervous system). although prior studies show these cells become activated during experimental alphavirus encephalitis in mice to generate cytokines and chemokines that influence virus replication, tissue inflammation and neuronal survival, the specific prrs (pattern recognition receptors) and signalling intermediates controlling microglial activation in this setti ...201222471445
atm kinase is activated by sindbis viral vector infection.sindbis virus is a prototypic member of the alphavirus genus, togaviridae family. sindbis replication results in cellular cytotoxicity, a feature that has been exploited by our laboratory for treatment of in vivo tumors. understanding the interactions between sindbis vectors and the host cell can lead to better virus production and increased efficacy of gene therapy vectors. here we present studies investigating a possible cellular response to genotoxic effects of sindbis vector infection. the a ...201222475743
dengue virus infection of the aedes aegypti salivary gland and chemosensory apparatus induces genes that modulate infection and blood-feeding behavior.the female aedes aegypti salivary gland plays a pivotal role in bloodmeal acquisition and reproduction, and thereby dengue virus (denv) transmission. it produces numerous immune factors, as well as immune-modulatory, vasodilatory, and anti-coagulant molecules that facilitate blood-feeding. to assess the impact of denv infection on salivary gland physiology and function, we performed a comparative genome-wide microarray analysis of the naïve and denv infection-responsive a. aegypti salivary gland ...201222479185
sindbis virus infectivity improves during the course of infection in both mammalian and mosquito cells.alphaviruses are enveloped, single-stranded positive sense rna viruses that are transmitted by an arthropod vector to a wide host range, including avian and mammalian species. arthropods and vertebrates have different cellular environments and this may cause the different cellular pathologies that are observed between the invertebrate vector and vertebrate hosts in both whole organisms and cultured cell lines. in this report, we used sindbis virus and examined mosquito and mammalian cell lines f ...201222484152
mitochondrial bioenergetic alterations in mouse neuroblastoma cells infected with sindbis virus: implications to viral replication and neuronal death.the metabolic resources crucial for viral replication are provided by the host. details of the mechanisms by which viruses interact with host metabolism, altering and recruiting high free-energy molecules for their own replication, remain unknown. sindbis virus, the prototype of and most widespread alphavirus, causes outbreaks of arthritis in humans and serves as a model for the study of the pathogenesis of neurological diseases induced by alphaviruses in mice. in this work, respirometric analys ...201222485151
usp18 promotes conventional cd11b+ dendritic cell development.dendritic cells (dcs) represent the key cells linking innate and adaptive immune responses. it is critical to understand the molecular factors regulating dc differentiation. usp18 is an ifn-inducible member of the ubiquitin-specific protease family, which deconjugates ubiquitin-like modifier isg15 from target proteins and competitively inhibits ifn-α/β-induced jak/stat activation. this study demonstrates that the frequency of conventional cd11b(+) dcs in the spleen of usp18(-/-) mice was signifi ...201222491252
epitope insertion at the n-terminal molecular switch of the rabbit hemorrhagic disease virus t = 3 capsid protein leads to larger t = 4 capsids.viruses need only one or a few structural capsid proteins to build an infectious particle. this is possible through the extensive use of symmetry and the conformational polymorphism of the structural proteins. using virus-like particles (vlp) from rabbit hemorrhagic disease virus (rhdv) as a model, we addressed the basis of calicivirus capsid assembly and their application in vaccine design. the rhdv capsid is based on a t=3 lattice containing 180 identical subunits (vp1). we determined the stru ...201222491457
determinants in the maturation of rubella virus p200 replicase polyprotein precursor.rubella virus (rubv), a positive-strand rna virus, replicates its rna within membrane-associated replication complexes (rcs) in the cytoplasm of infected cells. rna synthesis is mediated by the nonstructural proteins (nsps) p200 and its cleavage products, p150 and p90 (n and c terminal within p200, respectively), which are processed by a protease residing at the c terminus of p150. in this study of nsp maturation, we found that early nsp localization into foci appeared to target the membranes of ...201222491463
sindbis virus infection alters blood feeding responses and deet repellency in aedes aegypti (diptera: culicidae).aedes aegypti (l.) (diptera: culicidae) female mosquitoes infected systemically with sindbis virus (sinv) took longer than uninfected mosquitoes to locate and fully engorge on blood. on days 7 and 14 postexposure, blood feeding took 1.3 and 1.5 times longer in mosquitoes with a disseminated sinv infection, respectively. sinv dissemination did not affect the average weight of unfed ae. aegypti, but did result in a 10 and 12% increase in blood imbibed compared with mosquitoes without a positive si ...201222493862
phosphorylation of rpt6 regulates synaptic strength in hippocampal neurons.it has become increasingly evident that protein degradation via the ubiquitin proteasome system plays a fundamental role in the development, maintenance and remodeling of synaptic connections in the cns. we and others have recently described the activity-dependent regulation of proteasome activity and recruitment of proteasomes into spine compartments involving the phosphorylation of the 19s atpase subunit, rpt6, by the plasticity kinase ca(2+)/calmodulin-dependent protein kinase ii α (camkiiα) ...022496558
modulation of gsk-3β activity in venezuelan equine encephalitis virus infection.alphaviruses, including venezuelan equine encephalitis virus (veev), cause disease in both equine and humans that exhibit overt encephalitis in a significant percentage of cases. features of the host immune response and tissue-specific responses may contribute to fatal outcomes as well as the development of encephalitis. it has previously been shown that veev infection of mice induces transcription of pro-inflammatory cytokines genes (e.g., ifn-γ, il-6, il-12, inos and tnf-α) within 6 h. gsk-3β ...201222496857
chikungunya virus-induced autophagy delays caspase-dependent cell death.autophagy is an important survival pathway and can participate in the host response to infection. studying chikungunya virus (chikv), the causative agent of a major epidemic in india, southeast asia, and southern europe, we reveal a novel mechanism by which autophagy limits cell death and mortality after infection. we use biochemical studies and single cell multispectral assays to demonstrate that direct infection triggers both apoptosis and autophagy. chikv-induced autophagy is mediated by the ...201222508836
theranostic potential of oncolytic vaccinia virus.biological cancer therapies, such as oncolytic, or replication-selective viruses have advantages over traditional therapeutics as they can employ multiple different mechanisms to target and destroy cancers (including direct cell lysis, immune activation and vascular collapse). this has led to their rapid recent clinical development. however this also makes their pre-clinical and clinical study complex, as many parameters may affect their therapeutic potential and so defining reason for treatment ...201222509200
genetic and anatomic determinants of enzootic venezuelan equine encephalitis virus infection of culex (melanoconion) taeniopus.venezuelan equine encephalitis (vee) is a re-emerging, mosquito-borne viral disease with the potential to cause fatal encephalitis in both humans and equids. recently, detection of endemic vee caused by enzootic strains has escalated in mexico, peru, bolivia, colombia and ecuador, emphasizing the importance of understanding the enzootic transmission cycle of the etiologic agent, vee virus (veev). the majority of work examining the viral determinants of vector infection has been performed in the ...201222509419
glycogen synthase kinase 3β (gsk3β) modulates antiviral activity of zinc-finger antiviral protein (zap).zinc-finger antiviral protein (zap) is a host factor that specifically inhibits the replication of certain viruses, including hiv-1, ebola virus, and sindbis virus. zap binds directly to specific viral mrnas and recruits cellular mrna degradation machinery to degrade the target rna. zap has also been suggested to repress translation of the target mrna. in this study, we report that zap is phosphorylated by glycogen synthase kinase 3β (gsk3β). gsk3β sequentially phosphorylated ser-270, ser-266, s ...201222514281
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
aggrephagy: selective disposal of protein aggregates by macroautophagy.protein aggregation is a continuous process in our cells. some proteins aggregate in a regulated manner required for different vital functional processes in the cells whereas other protein aggregates result from misfolding caused by various stressors. the decision to form an aggregate is largely made by chaperones and chaperone-assisted proteins. proteins that are damaged beyond repair are degraded either by the proteasome or by the lysosome via autophagy. the aggregates can be degraded by the p ...201222518139
cell-based analysis of chikungunya virus e1 protein in membrane fusion.chikungunya fever is a pandemic disease caused by the mosquito-borne chikungunya virus (chikv). e1 glycoprotein mediation of viral membrane fusion during chikv infection is a crucial step in the release of viral genome into the host cytoplasm for replication. how the e1 structure determines membrane fusion and whether other chikv structural proteins participate in e1 fusion activity remain largely unexplored.201222520648
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
sumoylation and phosphorylation of gluk2 regulate kainate receptor trafficking and synaptic plasticity.phosphorylation or sumoylation of the kainate receptor (kar) subunit gluk2 have both individually been shown to regulate kar surface expression. however, it is unknown whether phosphorylation and sumoylation of gluk2 are important for activity-dependent kar synaptic plasticity. we found that protein kinase c–mediated phosphorylation of gluk2 at serine 868 promotes gluk2 sumoylation at lysine 886 and that both of these events are necessary for the internalization of gluk2-containing kars that occ ...022522402
clinical sindbis alphavirus infection is associated with hla-drb1*01 allele and production of autoantibodies.sindbis virus (sinv) is a mosquito-borne alphavirus found in eurasia, africa, and oceania. clinical sinv infection, characterized by arthropathic disease that may persist for years, is primarily reported in northern europe where the disease has considerable public health importance in endemic areas. the aim of this study was to investigate the role of genetic factors in the susceptibility and outcome of sinv infection and to elucidate the association between sinv infection and autoimmunity.201222523259
the n-end rule pathway.the n-end rule pathway is a proteolytic system in which n-terminal residues of short-lived proteins are recognized by recognition components (n-recognins) as essential components of degrons, called n-degrons. known n-recognins in eukaryotes mediate protein ubiquitylation and selective proteolysis by the 26s proteasome. substrates of n-recognins can be generated when normally embedded destabilizing residues are exposed at the n terminus by proteolytic cleavage. n-degrons can also be generated thr ...201222524314
interferon-inducible effector mechanisms in cell-autonomous immunity.interferons (ifns) induce the expression of hundreds of genes as part of an elaborate antimicrobial programme designed to combat infection in all nucleated cells - a process termed cell-autonomous immunity. as described in this review, recent genomic and subgenomic analyses have begun to assign functional properties to novel ifn-inducible effector proteins that restrict bacteria, protozoa and viruses in different subcellular compartments and at different stages of the pathogen life cycle. severa ...201222531325
amp-activated kinase restricts rift valley fever virus infection by inhibiting fatty acid synthesis.the cell intrinsic innate immune responses provide a first line of defense against viral infection, and often function by targeting cellular pathways usurped by the virus during infection. in particular, many viruses manipulate cellular lipids to form complex structures required for viral replication, many of which are dependent on de novo fatty acid synthesis. we found that the energy regulator ampk, which potently inhibits fatty acid synthesis, restricts infection of the bunyavirus, rift valle ...201222532801
avian influenza rapidly induces antiviral genes in duck lung and intestine.ducks are the natural reservoir of influenza a and survive infection by most strains. to characterize the duck immune response to influenza, we sought to identify innate immune genes expressed early in an infection. we used suppressive subtractive hybridization (ssh) to construct 3 libraries enriched in differentially expressed genes from lung rna of a duck infected with highly pathogenic avian influenza virus a/vietnam/1203/04 (h5n1), or lung and intestine rna of a duck infected with low pathog ...201222534314
membrane targeting of an alpha-like tetravirus replicase is directed by a region within the rna-dependent rna polymerase domain.the members of the family tetraviridae are small positive-sense insect rna viruses that exhibit stringent host specificity and a high degree of tissue tropism, suggesting that complex virus-host interactions are likely to occur during infection and viral replication. the alpha-like replicase of helicoverpa armigera stunt virus (hasv) (genus omegatetravirus) has been proposed to associate with membranes of the endocytic pathway, which is similar to semliki forest virus, sindbis virus and rubella ...201222535773
antibody-directed lentiviral gene transduction for live-cell monitoring and selection of human ips and hes cells.the identification of stem cells within a mixed population of cells is a major hurdle for stem cell biology--in particular, in the identification of induced pluripotent stem (ips) cells during the reprogramming process. based on the selective expression of stem cell surface markers, a method to specifically infect stem cells through antibody-conjugated lentiviral particles has been developed that can deliver both visual markers for live-cell imaging as well as selectable markers to enrich for ip ...201222536330
translational control of the activation of transcription factor nf-κb and production of type i interferon by phosphorylation of the translation factor eif4e.type i interferon is an integral component of the antiviral response, and its production is tightly controlled at the levels of transcription and translation. the eukaryotic translation-initiation factor eif4e is a rate-limiting factor whose activity is regulated by phosphorylation of ser209. here we found that mice and fibroblasts in which eif4e cannot be phosphorylated were less susceptible to virus infection. more production of type i interferon, resulting from less translation of nfkbia mrna ...201222544393
temperature and density-dependent effects of larval environment on aedes aegypti competence for an alphavirus.mosquito larvae experience multiple environmental stressors that may modify how subsequent adults interact with pathogens. we evaluated the effect of larval rearing temperature and intraspecific larval competition on adult mosquito immunity and vector competence for sindbis virus (sinv). aedes aegypti larvae were reared at two intraspecific densities (150 and 300 larvae) at 20° c and 30° c and the adults were fed artificially on citrated bovine blood containing 10(5) plaque forming units of sinv ...201222548549
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
arthritogenic alphaviruses--an overview.mosquito-transmitted alphaviruses causing human rheumatic disease are globally distributed and include chikungunya virus, ross river virus, barmah forest virus, sindbis virus, o'nyong-nyong virus and mayaro virus. these viruses cause endemic disease and, occasionally, large epidemics; for instance, the 2004-2011 chikungunya epidemic resulted in 1.4-6.5 million cases, with imported cases reported in nearly 40 countries. the disease is usually self-limiting and characterized by acute and chronic s ...201222565316
autophagy and mechanisms of effective immunity.macroautophagy (autophagy) is a cellular pathway facilitating several critical functions. first, autophagy is a major pathway of degradation. it enables elimination of microbes that have invaded intracellular compartments. in addition, it promotes degradation of damaged cellular content, thereby acting to limit inflammatory signals. second, autophagy is a major trafficking pathway, shuttling content between the cytosol and the lysosomal compartment. given these two key roles, autophagy can have ...201222566941
ebolavirus requires acid sphingomyelinase activity and plasma membrane sphingomyelin for infection.acid sphingomyelinase (asmase) converts the lipid sphingomyelin (sm) to phosphocholine and ceramide and has optimum activity at acidic ph. normally, asmase is located in lysosomes and endosomes, but membrane damage or the interaction with some bacterial and viral pathogens can trigger its recruitment to the plasma membrane. rhinovirus and measles viruses each require asmase activity during early stages of infection. both sphingomyelin and ceramide are important components of lipid rafts and are ...201222573858
a novel small molecule inhibitor of influenza a viruses that targets polymerase function and indirectly induces interferon.influenza viruses continue to pose a major public health threat worldwide and options for antiviral therapy are limited by the emergence of drug-resistant virus strains. the antiviral cytokine, interferon (ifn) is an essential mediator of the innate immune response and influenza viruses, like many viruses, have evolved strategies to evade this response, resulting in increased replication and enhanced pathogenicity. a cell-based assay that monitors ifn production was developed and applied in a hi ...201222577360
synthesis and antiviral evaluation of c5-substituted-(1,3-diyne)-2'-deoxyuridines.starting from acetylated 5-ethynyl-2'-deoxyuridine (3), 14 hitherto unknown c5-substituted-(1,3-diyne)-2'-deoxyuridines (with cyclopropyl, hydroxymethyl, methylcyclopentane, p-(substituted)phenyl and disubstituted-phenyl substituents) have been synthesized via a nickel-copper catalyzed c-h activation between two terminal alkynes, in yields ranging from 19% to 67%. their antiviral activities were measured against a large number of dna and rna viruses including herpes simplex virus type 1 and type ...201222578783
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
homeostatic synaptic scaling is regulated by protein sumoylation.homeostatic scaling allows neurons to alter synaptic transmission to compensate for changes in network activity. here, we show that suppression of network activity with tetrodotoxin, which increases surface expression of ampa receptors (ampars), dramatically reduces levels of the desumoylating (where sumo is small ubiquitin-like modifier) enzyme senp1, leading to a consequent increase in protein sumoylation. overexpression of the catalytic domain of senp1 prevents this scaling effect, and we ide ...201222582390
cross-protective immunity against o'nyong-nyong virus afforded by a novel recombinant chikungunya vaccine.emerging mosquito-borne alphavirus infections caused by chikungunya virus (chikv) or o'nyong-nyong virus (onnv) are responsible for sporadic and sometimes explosive urban outbreaks. currently, there is no licensed vaccine against either virus. we have developed a highly attenuated recombinant chikv candidate vaccine (chikv/ires) that in preclinical studies was demonstrated to be safe, immunogenic and efficacious. in this study we investigated the potential of this vaccine to induce cross-protect ...201222583812
pd-1/pd-l1 blockade can enhance hiv-1 gag-specific t cell immunity elicited by dendritic cell-directed lentiviral vaccines.exhaustion of cd8(+) t cells and upregulation of programmed death 1 (pd-1), a negative regulator of t cell activation, are characteristic features of individuals chronically infected with human immunodeficiency virus type 1. in a previous study, we showed in mice that a dendritic cell-directed lentiviral vector (dclv) system encoding the human immunodeficiency virus (hiv)-1 gag protein was an efficient vaccine modality to induce a durable gag-specific t cell immune response. in this study, we de ...201222588271
the contribution of rodent models to the pathological assessment of flaviviral infections of the central nervous system.members of the genus flavivirus are responsible for a spectrum of important neurological syndromes in humans and animals. rodent models have been used extensively to model flavivirus neurological disease, to discover host-pathogen interactions that influence disease outcome, and as surrogates to determine the efficacy and safety of vaccines and therapeutics. in this review, we discuss the current understanding of flavivirus neuroinvasive disease and outline the host, viral and experimental facto ...201222592957
s-scam/magi-2 is an essential synaptic scaffolding molecule for the glua2-containing maintenance pool of ampa receptors.synaptic plasticity, the cellular basis of learning and memory, involves the dynamic trafficking of ampa receptors (ampars) into and out of synapses. one of the remaining key unanswered aspects of ampar trafficking is the mechanism by which synaptic strength is preserved despite protein turnover. in particular, the identity of ampar scaffolding molecule(s) involved in the maintenance of glua2-containing ampars is completely unknown. here we report that the synaptic scaffolding molecule (s-scam; ...022593065
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
beneficial effects of fucoidan in patients with chronic hepatitis c virus infection.to evaluate the effects of fucoidan, a complex sulfated polysaccharide extract from marine seaweed, on hepatitis c virus (hcv) rna load both in vitro and in vivo.022611316
specific targeting of human interleukin (il)-13 receptor α2-positive cells with lentiviral vectors displaying il-13.the ability to selectively and efficiently target transgene delivery to specific cell types in vitro and in vivo remains one of the formidable challenges in gene therapy. lentiviral vectors have several advantages that make them attractive as gene delivery vehicles and their tropism can be altered through pseudotyping, allowing transgene delivery to specific populations of cells. the human interleukin-13 receptor α2 (il-13rα2) is uniquely overexpressed in many different human tumors, making it a ...201222612657
prolonged myalgia in sindbis virus infection: case description and in vitro infection of myotubes and myoblasts.sindbis virus (sinv) is a mosquito-borne alphavirus found in eurasia, africa, and oceania. clinical sinv infection is characterized by febrile rash and arthritis and sometimes prolonged arthralgia and myalgia. the pathophysiological mechanisms of musculoskeletal and rheumatic disease caused by sinv are inadequately understood.201222615321
induction of gadd34 is necessary for dsrna-dependent interferon-β production and participates in the control of chikungunya virus infection.nucleic acid sensing by cells is a key feature of antiviral responses, which generally result in type-i interferon production and tissue protection. however, detection of double-stranded rnas in virus-infected cells promotes two concomitant and apparently conflicting events. the dsrna-dependent protein kinase (pkr) phosphorylates translation initiation factor 2-alpha (eif2α) and inhibits protein synthesis, whereas cytosolic dexd/h box rna helicases induce expression of type i-ifn and other cytok ...201222615568
multiple interferon stimulated genes synergize with the zinc finger antiviral protein to mediate anti-alphavirus activity.the zinc finger antiviral protein (zap) is a host factor that mediates inhibition of viruses in the filoviridae, retroviridae and togaviridae families. we previously demonstrated that zap blocks replication of sindbis virus (sinv), the prototype alphavirus in the togaviridae family at an early step prior to translation of the incoming genome and that synergy between zap and one or more interferon stimulated genes (isgs) resulted in maximal inhibitory activity. the present study aimed to identify ...201222615998
the small hydrophobic protein of the human respiratory syncytial virus forms pentameric ion channels.the small hydrophobic (sh) protein is encoded by the human respiratory syncytial virus. its absence leads to viral attenuation in the context of whole organisms, and it prevents apoptosis in infected cells. herein, we have examined the structure of sh protein in detergent micelles and in lipid bilayers, by solution nmr and attenuated total reflection-fourier transform infrared spectroscopy, respectively. we found that sh protein has a single α-helical transmembrane domain and forms homopentamers ...201222621926
lack of interference with immunogenicity of a chimeric alphavirus replicon particle-based influenza vaccine by preexisting antivector immunity.antivector immunity has been recognized as a potential caveat of using virus-based vaccines. in the present study, an alphavirus-based replicon particle vaccine platform, which has demonstrated robust immunogenicity in animal models, was tested for effects of antivector immunity on immunogenicity against hemagglutinin of influenza virus as a target antigen and efficacy for protection against lethal challenge with the virus. chimeric alphavirus-based replicon particles, comprising venezuelan equi ...201222623651
orthobunyavirus entry into neurons and other mammalian cells occurs via clathrin-mediated endocytosis and requires trafficking into early endosomes.la crosse virus (lacv) is a leading cause of pediatric encephalitis and aseptic meningitis in the midwestern and southern united states, where it is considered an emerging human pathogen. no specific therapies or vaccines are available for lacv or any other orthobunyaviruses. inhibition of lacv entry into cells is a potential target for therapeutic intervention, but this approach is limited by our current knowledge of the entry process. here, we determined that clathrin-mediated endocytosis is t ...201222623766
herpes simplex virus 2 infection impacts stress granule accumulation.interference with stress granule (sg) accumulation is gaining increased appreciation as a common strategy used by diverse viruses to facilitate their replication and to cope with translational arrest. here, we examined the impact of infection by herpes simplex virus 2 (hsv-2) on sg accumulation by monitoring the localization of the sg components t cell internal antigen 1 (tia-1), ras-gtpase-activating sh3-domain-binding protein (g3bp), and poly(a)-binding protein (pabp). our results indicate tha ...201222623775
new parp gene with an anti-alphavirus function.alphaviruses represent a highly important group of human and animal pathogens, which are transmitted by mosquito vectors between vertebrate hosts. the hallmark of alphavirus infection in vertebrates is the induction of a high-titer viremia, which is strongly dependent on the ability of the virus to interfere with host antiviral responses on both cellular and organismal levels. the identification of cellular factors, which are critical in orchestrating virus clearance without the development of c ...201222623789
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
inhibition and avoidance of mrna degradation by rna viruses.the cellular mrna decay machinery plays a major role in regulating the quality and quantity of gene expression in cells. this machinery involves multiple enzymes and pathways that converge to promote the exonucleolytic decay of mrnas. the transcripts made by rna viruses are susceptible to degradation by this machinery and, in fact, can be actively targeted. thus, to maintain gene expression and replication, rna viruses have evolved a number of strategies to avoid and/or inactivate aspects of the ...201222626865
complete coding sequence and molecular epidemiological analysis of sindbis virus isolates from mosquitoes and humans, finland.sindbis virus (sinv) is an arthropod-borne alphavirus, which causes rash-arthritis, particularly in finland. sinv is transmitted by mosquitoes in finland but thus far no virus has been isolated from mosquitoes. in this study, we report the isolation of the first sinv strain from mosquitoes in finland and its full-length protein-coding sequence. we furthermore describe the full-length coding sequence of six sinv strains previously isolated from humans in finland and from a mosquito in russia. the ...201222647374
a specific domain of the chikungunya virus e2 protein regulates particle formation in human cells: implications for alphavirus vaccine design.virus-like particles (vlps) can be generated from chikungunya virus (chikv), but different strains yield variable quantities of particles. here, we define the genetic basis for these differences and show that amino acid 234 in e2 substantially affects vlp production. this site is located within the acid-sensitive region (asr) known to initiate a major conformational change in e1/e2. selected other mutations in the asr, or changes in ph, also increased vlp yield. these results demonstrate that th ...201222647698
recent insights into the involvement of progranulin in frontotemporal dementia.progranulin is a widely expressed protein that is involved in the regulation of multiple biological processes, including embryogenesis, host defense, and wound repair. in the central nervous system, progranulin is constitutively expressed at modest levels in neurons and microglia, but shows dramatic microglial immunoreactivity in degenerative diseases that exhibit prominent neuroinflammation. in addition to the role that pgrn plays in the periphery, its expression is of critical importance in br ...022654721
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
green tea polyphenol egcg sensing motif on the 67-kda laminin receptor.we previously identified the 67-kda laminin receptor (67lr) as the cell-surface receptor conferring the major green tea polyphenol (-)-epigallocatechin-3-o-gallate (egcg) responsiveness to cancer cells. however, the underlying mechanism for interaction between egcg and 67lr remains unclear. in this study, we investigated the possible role of egcg-67lr interaction responsible for its bioactivities.201222666419
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
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
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
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
sindbis virus replicase-based dna vaccine construct encoding fmdv-specific multivalent epitope gene: studies on its immune responses in guinea pigs.foot-and-mouth disease (fmd) is still a perennial global menace affecting livestock health and production. it is imperative to figure out new ways to curb this disease. in this study, a sindbis virus replicase-based dna vaccine, psincmv-vac-meg990, encoding a multivalent epitope gene (representing tandemly linked vp1 c-terminal halves of three foot-and-mouth disease virus (fmdv) serotypes) was constructed. in vitro transfection studies in bhk-21 cells revealed that the construct was able to expr ...201222702835
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
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
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
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
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
autophagy: an emerging immunological paradigm.autophagy is a fundamental eukaryotic process with multiple cytoplasmic homeostatic roles, recently expanded to include unique stand-alone immunological functions and interactions with nearly all parts of the immune system. in this article, we review this growing repertoire of autophagy roles in innate and adaptive immunity and inflammation. its unique functions include cell-autonomous elimination of intracellular microbes facilitated by specific receptors. other intersections of autophagy with ...022723639
is minocycline useful for therapy of acute viral encephalitis?minocyline is a tetracycline derivative with anti-inflammatory, anti-apoptotic, and anti-oxidant properties. therapy has proved useful in some experimental models of both noninfectious and infectious neurological diseases and also in clinical trials in humans, including acute traumatic cervical spinal cord injury. in models of viral encephalitis, treatment has shown both beneficial and deleterious effects. in reovirus infection in mice, minocycline delayed the disease, but did not improve either ...201222728256
amyloid-β peptide: dr. jekyll or mr. hyde?amyloid-β peptide (aβ) is considered a key protein in the pathogenesis of alzheimer's disease (ad) because of its neurotoxicity and capacity to form characteristic insoluble deposits known as senile plaques. aβ derives from amyloid-β protein precursor (aβpp), whose proteolytic processing generates several fragments including aβ peptides of various lengths. the normal function of aβpp and its fragments remains poorly understood. while some fragments have been suggested to have a function in norma ...022735675
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
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
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
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
Displaying items 4101 - 4200 of 5405