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antimicrobial autophagy: a conserved innate immune response in drosophila.autophagy is a highly conserved degradative pathway that has rapidly emerged as a critical component of immunity and host defense. studies have implicated autophagy genes in restricting the replication of a diverse array of pathogens, including bacteria, viruses and protozoans. however, in most cases, the in vivo role of antimicrobial autophagy against pathogens has been undefined. drosophila provides a genetically tractable model system that can be easily adapted to study autophagy in innate im ...201323689401
malaria infection does not affect the sensitivity of peripheral receptor neurons in anopheles stephensi.mosquitoes transmit many important diseases including malaria, dengue and yellow fever. disease transmission from one vertebrate host to another depends on repeated blood feedings by single mosquitoes. in order for the mosquito to acquire the blood that it needs to complete oogenesis, the insect must locate a suitable host. olfactory cues (including carbon dioxide) released by the host and detected by the mosquito are the primary signals that vector insects use for host location. previous studie ...201323642231
anti-hypertrophic and anti-oxidant effect of beta3-adrenergic stimulation in myocytes requires differential neuronal nos phosphorylation.stimulation of β3-adrenoreceptors (β3-ar) blunts contractility and improves chronic left ventricular function in hypertrophied and failing hearts in a neuronal nitric oxide synthase (nnos) dependent manner. nnos can be regulated by post-translational modification of stimulatory phosphorylation residue ser1412 and inhibitory residue ser847. however, the role of phosphorylation of these residues in cardiomyocytes and β3-ar protective signaling has yet to be explored.201323643588
fatal neurological respiratory insufficiency is common among viral encephalitides.neurological respiratory insufficiency strongly correlates with mortality among rodents infected with west nile virus (wnv), which suggests that this is a primary mechanism of death in rodents and possibly fatal west nile neurological disease in human patients.201323641019
autophagy and viruses: adversaries or allies?the autophagy pathway is an essential component of host defense against viral infection, orchestrating pathogen degradation (xenophagy), innate immune signaling, and certain aspects of adaptive immunity. single autophagy proteins or cassettes of the core autophagy machinery can also function as antiviral factors independently of the canonical autophagy pathway. moreover, to survive and propagate within the host, viruses have evolved a variety of strategies to evade autophagic attack and manipula ...201323391695
chloroquine inhibits dengue virus type 2 replication in vero cells but not in c6/36 cells.dengue viruses are the most important arthropod-borne viruses in terms of morbidity and mortality in the world. since there is no dengue vaccine available for human use, we have set out to investigate the use of chloroquine as an antiviral drug against dengue. chloroquine, an amine acidotropic drug known to affect intracellular exocytic pathways by increasing endosomal ph, was used in the in vitro treatment of vero and c6/36 cells infected with dengue virus type 2 (denv-2). real-time rt-pcr and ...201323431254
identification of a candidate therapeutic autophagy-inducing peptide.the lysosomal degradation pathway of autophagy has a crucial role in defence against infection, neurodegenerative disorders, cancer and ageing. accordingly, agents that induce autophagy may have broad therapeutic applications. one approach to developing such agents is to exploit autophagy manipulation strategies used by microbial virulence factors. here we show that a peptide, tat-beclin 1-derived from a region of the autophagy protein, beclin 1, which binds human immunodeficiency virus (hiv)-1 ...201323364696
differential unfolded protein response during chikungunya and sindbis virus infection: chikv nsp4 suppresses eif2α phosphorylation.chikungunya (chikv) and sindbis (sinv) are arboviruses belonging to the alphavirus genus within the togaviridae family. they cause frequent epidemics of febrile illness and long-term arthralgic sequelae that affect millions of people each year. both viruses replicate prodigiously in infected patients and in vitro in mammalian cells, suggesting some level of control over the host cellular translational machinery that senses and appropriately directs the cell's fate through the unfolded protein re ...201323356742
divergent roles of autophagy in virus infection.viruses have played an important role in human evolution and have evolved diverse strategies to co-exist with their hosts. as obligate intracellular pathogens, viruses exploit and manipulate different host cell processes, including cellular trafficking, metabolism and immunity-related functions, for their own survival. in this article, we review evidence for how autophagy, a highly conserved cellular degradative pathway, serves either as an antiviral defense mechanism or, alternatively, as a pro ...201324709646
ires-based venezuelan equine encephalitis vaccine candidate elicits protective immunity in mice.venezuelan equine encephalitis virus (veev) is an arbovirus that causes periodic outbreaks that impact equine and human populations in the americas. one of the veev subtypes located in mexico and central america (ie) has recently been recognized as an important cause of equine disease and death, and human exposure also appears to be widespread. here, we describe the use of an internal ribosome entry site (ires) from encephalomyocarditis virus to stably attenuate veev, creating a vaccine candidat ...201323351391
multiple functions of bcl-2 family proteins.bcl-2 family proteins are the regulators of apoptosis, but also have other functions. this family of interacting partners includes inhibitors and inducers of cell death. together they regulate and mediate the process by which mitochondria contribute to cell death known as the intrinsic apoptosis pathway. this pathway is required for normal embryonic development and for preventing cancer. however, before apoptosis is induced, bcl-2 proteins have critical roles in normal cell physiology related to ...201323378584
visualizing the autophagy pathway in avian cells and its application to studying infectious bronchitis virus.autophagy is a highly conserved cellular response to starvation that leads to the degradation of organelles and long-lived proteins in lysosomes and is important for cellular homeostasis, tissue development and as a defense against aggregated proteins, damaged organelles and infectious agents. although autophagy has been studied in many animal species, reagents to study autophagy in avian systems are lacking. microtubule-associated protein 1 light chain 3 (map1lc3/lc3) is an important marker for ...201323328491
crystal structure of glycoprotein c from rift valley fever virus.rift valley fever virus (rvfv), like many other bunyaviridae family members, is an emerging human and animal pathogen. bunyaviruses have an outer lipid envelope bearing two glycoproteins, g(n) and g(c), required for cell entry. bunyaviruses deliver their genome into the host-cell cytoplasm by fusing their envelope with an endosomal membrane. the molecular mechanism of this key entry step is unknown. the crystal structure of rvfv g(c) reveals a class ii fusion protein architecture found previousl ...201323319635
ifn production ability and healthy ageing: mixed model analysis of a 24 year longitudinal study in japan.to track changes in interferon (ifn) production in healthy individuals to shed light on the effect these changes have on the course of healthy ageing.201323315513
sumoylation is required for glycine-induced increases in ampa receptor surface expression (chemltp) in hippocampal neurons.multiple pathways participate in the ampa receptor trafficking that underlies long-term potentiation (ltp) of synaptic transmission. here we demonstrate that protein sumoylation is required for insertion of the glua1 ampar subunit following transient glycine-evoked increase in ampa receptor surface expression (chemltp) in dispersed neuronal cultures. chemltp increases co-localisation of sumo-1 and the sumo conjugating enzyme ubc9 and with psd95 consistent with the recruitment of sumoylated prote ...201323326329
alphavirus genome delivery occurs directly at the plasma membrane in a time- and temperature-dependent process.it is widely held that arboviruses such as the alphavirus sindbis virus gain entry into cells by a process of receptor-mediated endocytosis followed by membrane fusion in the acid environment of the endosome. we have used an approach of direct observation of sindbis virus entry into cells by electron microscopy and immunolabeling of virus proteins with antibodies conjugated to gold beads. we found that upon attaching to the cell surface, intact rna-containing viruses became empty shells that cou ...201323388718
an antiviral role for antimicrobial peptides during the arthropod response to alphavirus replication.alphaviruses establish a persistent infection in arthropod vectors which is essential for the effective transmission of the virus to vertebrate hosts. the development of persistence in insects is not well understood, although it is thought to involve the innate immune response. using a transgenic fly system expressing a self-replicating viral rna genome analog, we have previously demonstrated antiviral roles of the drosophila imd (immune deficiency) and jak-stat innate immunity pathways in respo ...201323365449
an rna element in human interleukin 6 confers escape from degradation by the gammaherpesvirus sox protein.several viruses express factors to silence host gene expression via widespread mrna degradation. this phenotype is the result of the coordinated activity of the viral endonuclease sox and the cellular rna degradation enzyme xrn1 during lytic kaposi's sarcoma-associated herpesvirus (kshv) infection. while most cellular transcripts are highly downregulated, a subset of host mrna escapes turnover via unknown mechanisms. one of the most prominent escapees is the interleukin 6 (il-6) mrna, which accu ...201323408619
venezuelan equine encephalitis virus nsp2 protein regulates packaging of the viral genome into infectious virions.alphaviruses are one of the most geographically widespread and yet often neglected group of human and animal pathogens. they are capable of replicating in a wide variety of cells of both vertebrate and insect origin and are widely used for the expression of heterologous genetic information both in vivo and in vitro. in spite of their use in a range of research applications and their recognition as a public health threat, the biology of alphaviruses is insufficiently understood. in this study, we ...201323365438
5-(perylen-3-yl)ethynyl-arabino-uridine (auy11), an arabino-based rigid amphipathic fusion inhibitor, targets virion envelope lipids to inhibit fusion of influenza virus, hepatitis c virus, and other enveloped viruses.entry of enveloped viruses requires fusion of viral and cellular membranes. fusion requires the formation of an intermediate stalk structure, in which only the outer leaflets are fused. the stalk structure, in turn, requires the lipid bilayer of the envelope to bend into negative curvature. this process is inhibited by enrichment in the outer leaflet of lipids with larger polar headgroups, which favor positive curvature. accordingly, phospholipids with such shape inhibit viral fusion. we previou ...201323283943
novel benzoxazole inhibitor of dengue virus replication that targets the ns3 helicase.dengue virus (denv) is the predominant mosquito-borne viral pathogen that infects humans with an estimated 50 to 100 million infections per year worldwide. over the past 50 years, the incidence of dengue disease has increased dramatically and the virus is now endemic in more than 100 countries. moreover, multiple serotypes of denv are now found in the same geographic region, increasing the likelihood of more severe forms of disease. despite extensive research, there are still no approved vaccine ...201323403421
a ubiquitin-specific protease possesses a decisive role for adenovirus replication and oncogene-mediated transformation.adenoviral replication depends on viral as well as cellular proteins. however, little is known about cellular proteins promoting adenoviral replication. in our screens to identify such proteins, we discovered a cellular component of the ubiquitin proteasome pathway interacting with the central regulator of adenoviral replication. our binding assays mapped a specific interaction between the n-terminal domains of both viral e1b-55k and usp7, a deubiquitinating enzyme. rna interference-mediated dow ...201323555268
molecular determinants of mouse neurovirulence and mosquito infection for western equine encephalitis virus.western equine encephalitis virus (weev) is a naturally occurring recombinant virus derived from ancestral sindbis and eastern equine encephalitis viruses. we previously showed that infection by weev isolates mcmillan (mcm) and imp-181 (imp) results in high (∼90-100%) and low (0%) mortality, respectively, in outbred cd-1 mice when virus is delivered by either subcutaneous or aerosol routes. however, relatively little is known about specific virulence determinants of weev. we previously observed ...201323544138
evolution of sindbis virus with a low-methionine-resistant phenotype is dependent both on a pre-existing mutation and on the methionine concentration in the medium.svlm21 is a mutant of sindbis virus which was isolated by serial passage of virus in mosquito cells maintained in low-methionine medium; it therefore has a low-methionine-resistant (lmr) phenotype. this phenotype requires mutations at nts 319 and 321; these mutations result in arg to leu and ser to cys changes at positions 87 and 88 respectively in the viral methyl transferase, nsp1. to better understand the genesis of svlm21, we carried out serial passages of viruses having only one of these am ...201323544150
baculovirus-mediated gene transfer in butterfly wings in vivo: an efficient expression system with an anti-gp64 antibody.candidate genes for color pattern formation in butterfly wings have been known based on gene expression patterns since the 1990s, but their functions remain elusive due to a lack of a functional assay. several methods of transferring and expressing a foreign gene in butterfly wings have been reported, but they have suffered from low success rates or low expression levels. here, we developed a simple, practical method to efficiently deliver and express a foreign gene using baculovirus-mediated ge ...201323522444
adaptation of enterovirus 71 to adult interferon deficient mice.non-polio enteroviruses, including enterovirus 71 (ev71), have caused severe and fatal cases of hand, foot and mouth disease (hfmd) in the asia-pacific region. the development of a vaccine or antiviral against these pathogens has been hampered by the lack of a reliable small animal model. in this study, a mouse adapted ev71 strain was produced by conducting serial passages through a129 (α/β interferon (ifn) receptor deficient) and ag129 (α/β, γ ifn receptor deficient) mice. a b2 sub genotype of ...201323527208
moving h5n1 studies into the era of systems biology.the dynamics of h5n1 influenza virus pathogenesis are multifaceted and can be seen as an emergent property that cannot be comprehended without looking at the system as a whole. in past years, most of the high-throughput studies on h5n1-host interactions have focused on the host transcriptomic response, at the cellular or the lung tissue level. these studies pointed out that the dynamics and magnitude of the innate immune response and immune cell infiltration is critical to h5n1 pathogenesis. how ...201323499671
intracellular antibody-bound pathogens stimulate immune signaling via the fc receptor trim21.during pathogen infection, antibodies can be carried into the infected cell, where they are detected by the ubiquitously expressed cytosolic antibody receptor trim21. here we found that recognition of intracellular antibodies by trim21 activated immune signaling. trim21 catalyzed the formation of lys63 (k63)-linked ubiquitin chains and stimulated the transcription factor pathways of nf-κb, ap-1, irf3, irf5 and irf7. activation resulted in the production of proinflammatory cytokines, modulation o ...201323455675
differential innate immune response programs in neuronal subtypes determine susceptibility to infection in the brain by positive-stranded rna viruses.although susceptibility of neurons in the brain to microbial infection is a major determinant of clinical outcome, little is known about the molecular factors governing this vulnerability. here we show that two types of neurons from distinct brain regions showed differential permissivity to replication of several positive-stranded rna viruses. granule cell neurons of the cerebellum and cortical neurons from the cerebral cortex have unique innate immune programs that confer differential susceptib ...201323455712
astrocyte-derived cxcl10 drives accumulation of antibody-secreting cells in the central nervous system during viral encephalomyelitis.microbial infections of the central nervous system (cns) are often associated with local accumulation of antibody (ab)-secreting cells (asc). by providing a source of ab at the site of infection, cns-localized asc play a critical role in acute viral control and in preventing viral recrudescence. following coronavirus-induced encephalomyelitis, the cns accumulation of asc is chemokine (c-x-c motif) receptor 3 (cxcr3) dependent. this study demonstrates that cns-expressed cxcr3 ligand cxcl10 is the ...201323302888
filoviruses utilize glycosaminoglycans for their attachment to target cells.filoviruses are the cause of severe hemorrhagic fever in human and nonhuman primates. the envelope glycoprotein (gp), responsible for both receptor binding and fusion of the virus envelope with the host cell membrane, has been demonstrated to interact with multiple molecules in order to enhance entry into host cells. here we have demonstrated that filoviruses utilize glycosaminoglycans, and more specifically heparan sulfate proteoglycans, for their attachment to host cells. this interaction is m ...201323302881
norwalk virus minor capsid protein vp2 associates within the vp1 shell domain.the major capsid protein of norovirus vp1 assembles to form an icosahedral viral particle. despite evidence that the norwalk virus (nv) minor structural protein vp2 is present in infectious virions, the available crystallographic and electron cryomicroscopy structures of nv have not revealed the location of vp2. in this study, we determined that vp1 associates with vp2 at the interior surface of the capsid, specifically with the shell (s) domain of vp1. we mapped the interaction site to amino ac ...201323408637
hierarchy of orofacial rhythms revealed through whisking and breathing.whisking and sniffing are predominant aspects of exploratory behaviour in rodents. yet the neural mechanisms that generate and coordinate these and other orofacial motor patterns remain largely uncharacterized. here we use anatomical, behavioural, electrophysiological and pharmacological tools to show that whisking and sniffing are coordinated by respiratory centres in the ventral medulla. we delineate a distinct region in the ventral medulla that provides rhythmic input to the facial motor neur ...201323624373
postsynaptic kainate receptor recycling and surface expression are regulated by metabotropic autoreceptor signalling.kainate receptors (kars) play fundamentally important roles in controlling synaptic function and regulating neuronal excitability. postsynaptic kars contribute to excitatory neurotransmission but the molecular mechanisms underlying their activity-dependent surface expression are not well understood. strong activation of kars in cultured hippocampal neurons leads to the downregulation of postsynaptic kars via endocytosis and degradation. in contrast, low-level activation augments postsynaptic kar ...201323556457
a mobile genetic element with unknown function found in distantly related viruses.the genetic element s2m seems to represent one of very few examples of mobile genetic elements in viruses. the function remains obscure and a scattered taxonomical distribution has been reported by numerous groups.201323618040
nmda receptor subunit composition determines beta-amyloid-induced neurodegeneration and synaptic loss.aggregates of amyloid-beta (aβ) and tau are hallmarks of alzheimer's disease (ad) leading to neurodegeneration and synaptic loss. while increasing evidence suggests that inhibition of n-methyl-d-aspartate receptors (nmdars) may mitigate certain aspects of ad neuropathology, the precise role of different nmdar subtypes for aβ- and tau-mediated toxicity remains to be elucidated. using mouse organotypic hippocampal slice cultures from arcaβ transgenic mice combined with sindbis virus-mediated expre ...201323618906
the protective roles of autophagy in ischemic preconditioning.autophagy, a process for the degradation of protein aggregates and dysfunctional organelles, is required for cellular homeostasis and cell survival in response to stress and is implicated in endogenous protection. ischemic preconditioning is a brief and nonlethal episode of ischemia, confers protection against subsequent ischemia-reperfusion through the up-regulation of endogenous protective mechanisms. emerging evidence shows that autophagy is associated with the protective effect of ischemic p ...201323603984
membrane curvature in flaviviruses.coordinated interplay between membrane proteins and the lipid bilayer is required for such processes as transporter function and the entrance of enveloped viruses into host cells. in this study, three-dimensional cryo-electron microscopy density maps of mature and immature flaviviruses were analyzed to assess the curvature of the membrane leaflets and its relation to membrane-bound viral glycoproteins. the overall morphology of the viral membrane is determined by the icosahedral scaffold compose ...201323602814
viral precursor polyproteins: keys of regulation from replication to maturation.many viruses use a replication strategy involving the translation of a large polyprotein, which is cleaved by viral and/or cellular proteases. several of these viruses severely impact human health around the globe, including hiv, hcv, dengue virus, and west nile virus. this method of genome organization has many benefits to the virus such as condensation of genetic material, as well as temporal and spatial regulation of protein activity depending on polyprotein cleavage state. the study of polyp ...201323602469
do viruses require the cytoskeleton?it is generally thought that viruses require the cytoskeleton during their replication cycle. however, recent experiments in our laboratory with rubella virus, a member of the family togaviridae (genus rubivirus), revealed that replication proceeded in the presence of drugs that inhibit microtubules. this study was done to expand on this observation.201323597412
postexit surface engineering of retroviral/lentiviral vectors.gene delivery vectors based on retroviral or lentiviral particles are considered powerful tools for biomedicine and biotechnology applications. such vectors require modification at the genomic level in the form of rearrangements to allow introduction of desired genes and regulatory elements (genotypic modification) as well as engineering of the physical virus particle (phenotypic modification) in order to mediate efficient and safe delivery of the genetic information to the target cell nucleus. ...201323691494
chikungunya virus host range e2 transmembrane deletion mutants induce protective immunity against challenge in c57bl/6j mice.a vaccine against chikungunya virus (chikv), a reemerging pathogenic arbovirus, has been made by attenuating wild-type (wt) virus via truncation of the transmembrane domain (tmd) of e2 and selecting for host range (hr) mutants. mice are a standard model system for chikv disease and display the same symptoms of the disease seen in humans. groups of mice were inoculated with one of three chikv hr mutants to determine the ability of each mutant strain to elicit neutralizing antibody and protective ...201323552427
the receptor attachment function of measles virus hemagglutinin can be replaced with an autonomous protein that binds her2/neu while maintaining its fusion-helper function.cell entry of enveloped viruses is initiated by attachment to the virus receptor followed by fusion between the virus and host cell membranes. measles virus (mv) attachment to its receptor is mediated by the hemagglutinin (h), which is thought to produce conformational changes in the membrane fusion protein (f) that trigger insertion of its fusion peptide into the target cell membrane. here, we uncoupled receptor attachment and the fusion-helper function of h by introducing y481a, r533a, s548l, ...201323536664
mda5 localizes to stress granules, but this localization is not required for the induction of type i interferon.virus infection can initiate a type i interferon (ifn-α/β) response via activation of the cytosolic rna sensors retinoic acid-inducible gene-i (rig-i) and melanoma differentiation-associated gene 5 (mda5). furthermore, it can activate kinases that phosphorylate eukaryotic translation initiation factor 2α (eif2α), which leads to inhibition of (viral) protein translation and formation of stress granules (sg). most viruses have evolved mechanisms to suppress these cellular responses. here, we show ...201323536668
oncolytic virotherapy: the questions and the promise.oncolytic virotherapy is a new strategy to reduce tumor burden through selective virus replication in rapidly proliferating cells. oncolytic viruses are members of at least ten virus families, each with its advantages and disadvantages. here, i briefly review the recent advances and key challenges, as exemplified by the best-studied platforms. recent advances include preclinical proof of feasibility, clinical evidence of tolerability and effectiveness, and the development of new strategies to im ...201327512655
inducible interleukin 32 (il-32) exerts extensive antiviral function via selective stimulation of interferon λ1 (ifn-λ1).interleukin (il)-32 has been recognized as a proinflammatory cytokine that participates in responses to viral infection. however, little is known about how il-32 is induced in response to viral infection and the mechanisms of il-32-mediated antiviral activities. we discovered that il-32 is elevated by hepatitis b virus (hbv) infection both in vitro and in vivo and that hbv induced il-32 expression at the level of both transcription and post-transcription. furthermore, microrna-29b was found to b ...201323729669
hepatitis e: molecular virology and pathogenesis.hepatitis e virus is a single, positive-sense, capped and poly a tailed rna virus classified under the family hepeviridae. enteric transmission, acute self-limiting hepatitis, frequent epidemic and sporadic occurrence, high mortality in affected pregnants are hallmarks of hepatitis e infection. lack of an efficient culture system and resulting reductionist approaches for the study of replication and pathogenesis of hev made it to be a less understood agent. early studies on animal models, sub-ge ...201325755485
iron absorption in drosophila melanogaster.the way in which drosophila melanogaster acquires iron from the diet remains poorly understood despite iron absorption being of vital significance for larval growth. to describe the process of organismal iron absorption, consideration needs to be given to cellular iron import, storage, export and how intestinal epithelial cells sense and respond to iron availability. here we review studies on the divalent metal transporter-1 homolog malvolio (iron import), the recent discovery that multicopper o ...201323686013
in vivo bioluminescent imaging of influenza a virus infection and characterization of novel cross-protective monoclonal antibodies.influenza a virus is a major human pathogen responsible for seasonal epidemics as well as pandemic outbreaks. due to the continuing burden on human health, the need for new tools to study influenza virus pathogenesis as well as to evaluate new therapeutics is paramount. we report the development of a stable, replication-competent luciferase reporter influenza a virus that can be used for in vivo imaging of viral replication. this imaging is noninvasive and allows for the longitudinal monitoring ...201323698304
natural variation in the heparan sulfate binding domain of the eastern equine encephalitis virus e2 glycoprotein alters interactions with cell surfaces and virulence in mice.recently, we compared amino acid sequences of the e2 glycoprotein of natural north american eastern equine encephalitis virus (na-eeev) isolates and demonstrated that naturally circulating viruses interact with heparan sulfate (hs) and that this interaction contributes to the extreme neurovirulence of eeev (c. l. gardner, g. d. ebel, k. d. ryman, and w. b. klimstra, proc. natl. acad. sci. u. s. a., 108:16026-16031, 2011). in the current study, we have examined the contribution to hs binding of e ...201323720725
activity increase in respiratory chain complexes by rubella virus with marginal induction of oxidative stress.mitochondria are important for the viral life cycle, mainly by providing the energy required for viral replication and assembly. a highly complex interaction with mitochondria is exerted by rubella virus (rv), which includes an increase in the mitochondrial membrane potential as a general marker for mitochondrial activity. we aimed in this study to provide a more comprehensive picture of the activity of mitochondrial respiratory chain complexes i to iv. their activities were compared among three ...201323720730
possible role of a cell surface carbohydrate in evolution of resistance to viral infections in old world primates.due to inactivation of the α1,3-galactosyltransferase gene (ggta1, or the α1,3gt gene) approximately 28 million years ago, the carbohydrate αgal (galα1,3galβ1,4glcnac) is not expressed on the cells of old world monkeys and apes (including humans) but is expressed in all other mammals. the proposed selective advantage of this mutation for these primates is the ability to produce anti-gal antibodies, which may be an effective immune component in neutralizing αgal-expressing pathogens. however, los ...201323740988
fusion of mapple and venus fluorescent proteins to the sindbis virus e2 protein leads to different cell-binding properties.fluorescent proteins (fps) are widely used in real-time single virus particle studies to visualize, track and quantify the spatial and temporal parameters of viral pathways. however, potential functional differences between the wild type and the fp-tagged virus may specifically affect particular stages in the virus life-cycle. in this work, we genetically modified the e2 spike protein of sindbis virus (sinv) with two fps. we inserted mapple, a red fp, or venus, a yellow fp, at the n-terminus of ...201323916968
inhibition of hiv-1 replication by secondary metabolites from endophytic fungi of desert plants.most antiretroviral drugs currently in use to treat an hiv-1 infection are chemically synthesized and lead to the development of viral resistance, as well as cause severe toxicities. however, a largely unexplored source for hiv-1 drug discovery is endophytic fungi that live in a symbiotic relationship with plants. these fungi produce biologically active secondary metabolites, which are natural products that are beneficial to the host. we prepared several hundred extracts from endophytic fungi of ...201323961302
flaviviruses are sensitive to inhibition of thymidine synthesis pathways.dengue virus has emerged as a global health threat to over one-third of humankind. as a positive-strand rna virus, dengue virus relies on the host cell metabolism for its translation, replication, and egress. therefore, a better understanding of the host cell metabolic pathways required for dengue virus infection offers the opportunity to develop new approaches for therapeutic intervention. in a recently described screen of known drugs and bioactive molecules, we observed that methotrexate and f ...201323824813
encephalomyocarditis virus disrupts stress granules, the critical platform for triggering antiviral innate immune responses.in response to stress, cells induce ribonucleoprotein aggregates, termed stress granules (sgs). sgs are transient loci containing translation-stalled mrna, which is eventually degraded or recycled for translation. infection of some viruses, including influenza a virus with a deletion of nonstructural protein 1 (iavδns1), induces sg-like protein aggregates. previously, we showed that iavδns1-induced sgs are required for efficient induction of type i interferon (ifn). here, we investigated sg form ...201323785203
heterogeneous nuclear ribonucleoprotein k supports vesicular stomatitis virus replication by regulating cell survival and cellular gene expression.the heterogeneous nuclear ribonucleoprotein k (hnrnp k) is a member of the family of hnrnps and was recently shown in a genome-wide small interfering rna (sirna) screen to support vesicular stomatitis virus (vsv) growth. to decipher the role of hnrnp k in vsv infection, we conducted studies which suggest that the protein is required for vsv spreading. virus binding to cells, entry, and nucleocapsid uncoating steps were not adversely affected in the absence of hnrnp k, whereas viral genome transc ...201323843646
zebrafish isg15 exerts a strong antiviral activity against rna and dna viruses and regulates the interferon response.isg15, a 15-kda interferon-induced protein that participates in antiviral defenses of mammals, is highly conserved among vertebrates. in fish, as in mammals, viral infection and interferon treatment induce isg15 expression. the two ubiquitin-like domains of isg15 and the presence of a consensus lrlrgg sequence in the c-terminal region, which is required for the covalent conjugation to a substrate protein, are also conserved in fish. our data demonstrate that overexpression of zebrafish isg15 (zf ...201323824820
functional specialization of the small interfering rna pathway in response to virus infection.in drosophila, post-transcriptional gene silencing occurs when exogenous or endogenous double stranded rna (dsrna) is processed into small interfering rnas (sirnas) by dicer-2 (dcr-2) in association with a dsrna-binding protein (dsrbp) cofactor called loquacious (loqs-pd). sirnas are then loaded onto argonaute-2 (ago2) by the action of dcr-2 with another dsrbp cofactor called r2d2. loaded ago2 executes the destruction of target rnas that have sequence complementarity to sirnas. although dcr-2, r ...201324009507
non-encapsidation activities of the capsid proteins of positive-strand rna viruses.viral capsid proteins (cps) are characterized by their role in forming protective shells around viral genomes. however, cps have additional and important roles in the virus infection cycles and in the cellular responses to infection. these activities involve cp binding to rnas in both sequence-specific and nonspecific manners as well as association with other proteins. this review focuses on cps of both plant and animal-infecting viruses with positive-strand rna genomes. we summarize the structu ...201324074574
erk signaling couples nutrient status to antiviral defense in the insect gut.a unique facet of arthropod-borne virus (arbovirus) infection is that the pathogens are orally acquired by an insect vector during the taking of a blood meal, which directly links nutrient acquisition and pathogen challenge. we show that the nutrient responsive erk pathway is both induced by and restricts disparate arboviruses in drosophila intestines, providing insight into the molecular determinants of the antiviral "midgut barrier." wild-type flies are refractory to oral infection by arboviru ...201323980175
enhanced delivery and potency of self-amplifying mrna vaccines by electroporation in situ.nucleic acid-based vaccines such as viral vectors, plasmid dna (pdna), and mrna are being developed as a means to address limitations of both live-attenuated and subunit vaccines. dna vaccines have been shown to be potent in a wide variety of animal species and several products are now licensed for commercial veterinary but not human use. electroporation delivery technologies have been shown to improve the generation of t and b cell responses from synthetic dna vaccines in many animal species an ...201326344119
replication vesicles are load- and choke-points in the hepatitis c virus lifecycle.hepatitis c virus (hcv) infection develops into chronicity in 80% of all patients, characterized by persistent low-level replication. to understand how the virus establishes its tightly controlled intracellular rna replication cycle, we developed the first detailed mathematical model of the initial dynamic phase of the intracellular hcv rna replication. we therefore quantitatively measured viral rna and protein translation upon synchronous delivery of viral genomes to host cells, and thoroughly ...201323990783
detection of dengue viruses using reverse transcription-loop-mediated isothermal amplification.early and rapid detection of dengue virus (denv) infection during the febrile period is crucial for proper patient management and prevention of disease spread. an easy to perform and highly sensitive method is needed for routine implementation especially in the resource-limited rural healthcare settings where dengue is endemic.201323964963
coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics.no therapeutics or vaccines currently exist for human coronaviruses (hcovs). the severe acute respiratory syndrome-associated coronavirus (sars-cov) epidemic in 2002-2003, and the recent emergence of middle east respiratory syndrome coronavirus (mers-cov) in april 2012, emphasize the high probability of future zoonotic hcov emergence causing severe and lethal human disease. additionally, the resistance of sars-cov to ribavirin (rbv) demonstrates the need to define new targets for inhibition of c ...201323966862
isolation of midgut escape mutants of two american genotype dengue 2 viruses from aedes aegypti.several studies have shown that american genotype dengue 2 viruses (denv2) have reduced viral fitness in the mosquito vector, aedes aegypti, compared to other denv2 genotypes. diminished replication efficiency or inability to efficiently traverse membrane barriers encompassing organs such as the midgut or salivary glands are considered major factors negatively impacting viral fitness in the mosquito.201323937713
amalgamating oncolytic viruses to enhance their safety, consolidate their killing mechanisms, and accelerate their spread.oncolytic viruses are structurally and biologically diverse, spreading through tumors and killing them by various mechanisms and with different kinetics. here, we created a hybrid vesicular stomatitis/measles virus (vsv/mv) that harnesses the safety of oncolytic mv, the speed of vsv, and the tumor killing mechanisms of both viruses. oncolytic mv targets cd46 and kills by forcing infected cells to fuse with uninfected neighbors, but propagates slowly. vsv spreads rapidly, directly lysing tumor ce ...201323842448
viral vectors for vaccine applications.traditional approach of inactivated or live-attenuated vaccine immunization has resulted in impressive success in the reduction and control of infectious disease outbreaks. however, many pathogens remain less amenable to deal with the traditional vaccine strategies, and more appropriate vaccine strategy is in need. recent discoveries that led to increased understanding of viral molecular biology and genetics has rendered the used of viruses as vaccine platforms and as potential anti-cancer agent ...201323858400
map1b-dependent rac activation is required for ampa receptor endocytosis during long-term depression.the microtubule-associated protein 1b (map1b) plays critical roles in neurite growth and synapse maturation during brain development. this protein is well expressed in the adult brain. however, its function in mature neurons remains unknown. we have used a genetically modified mouse model and shrna techniques to assess the role of map1b at established synapses, bypassing map1b functions during neuronal development. under these conditions, we found that map1b deficiency alters synaptic plasticity ...201323881099
viral evasion mechanisms of early antiviral responses involving regulation of ubiquitin pathways.early innate and cell-intrinsic responses are essential to protect host cells against pathogens. in turn, viruses have developed sophisticated mechanisms to establish productive infections by counteracting host innate immune responses. increasing evidence indicates that these antiviral factors may have a dual role by directly inhibiting viral replication as well as by sensing and transmitting signals to induce antiviral cytokines. recent studies have pointed at new, unappreciated mechanisms of v ...201323850008
active vaccination with vaccinia virus a33 protects mice against lethal vaccinia and ectromelia viruses but not against cowpoxvirus; elucidation of the specific adaptive immune response.vaccinia virus protein a33 (a33vacv) plays an important role in protection against orthopoxviruses, and hence is included in experimental multi-subunit smallpox vaccines. in this study we show that single-dose vaccination with recombinant sindbis virus expressing a33vacv, is sufficient to protect mice against lethal challenge with vaccinia virus wr (vacv-wr) and ectromelia virus (ectv) but not against cowpox virus (cpxv), a closely related orthopoxvirus. moreover, a subunit vaccine based on the ...201323842430
lipidome analysis of rotavirus-infected cells confirms the close interaction of lipid droplets with viroplasms.rotaviruses (rvs) cause acute gastroenteritis in infants and young children, and are globally distributed. within the infected host cell, rvs establish replication complexes in viroplasms ('viral factories') to which lipid droplet organelles are recruited. to further understand this recently discovered phenomenon, the lipidomes of rv-infected and uninfected ma104 cells were investigated. cell lysates were subjected to equilibrium ultracentrifugation through iodixanol gradients. fourteen differen ...201323515026
visualization of dc-sign-mediated entry pathway of engineered lentiviral vectors in target cells.dendritic cells (dcs) are potent antigen-presenting cells and therefore have enormous potential as vaccine targets. we have previously developed an engineered lentiviral vector (lv) that is pseudotyped with a mutated sindbis virus glycoprotein (svgmu), which is capable of targeting dcs through dendritic cell-specific icam3-grabbing nonintegrin (dc-sign), a receptor that is predominantly expressed by dcs. in this study, we aimed to elucidate the internalization and trafficking mechanisms of this ...201323840690
induction of apoptosis in mcf-7 cells by the hemagglutinin-neuraminidase glycoprotein of newcastle disease virus malaysian strain af2240.newcastle disease virus (ndv) exerts its naturally occurring oncolysis possibly through the induction of apoptosis. we hypothesized that the binding of the virus to the cell via the hemagglutinin-neuraminidase (hn) glycoprotein may be sufficient to not only induce apoptosis but to induce a higher apoptosis level than the parental ndv af2240 virus. ndv af2240 induction of apoptosis in mcf-7 human breast cancer cells was analyzed and quantified. in addition, the complete hn gene of ndv strain af22 ...201323807159
mature neurons: equipped for survival.neurons completely transform how they regulate cell death over the course of their lifetimes. developing neurons freely activate cell death pathways to fine-tune the number of neurons that are needed during the precise formation of neural networks. however, the regulatory balance between life and death shifts as neurons mature beyond early development. mature neurons promote survival at all costs by employing multiple, often redundant, strategies to prevent cell death by apoptosis. this dramatic ...201323807218
understanding and altering cell tropism of vesicular stomatitis virus.vesicular stomatitis virus (vsv) is a prototypic nonsegmented negative-strand rna virus. vsv's broad cell tropism makes it a popular model virus for many basic research applications. in addition, a lack of preexisting human immunity against vsv, inherent oncotropism and other features make vsv a widely used platform for vaccine and oncolytic vectors. however, vsv's neurotropism that can result in viral encephalitis in experimental animals needs to be addressed for the use of the virus as a safe ...201323796410
a short hairpin rna screen of interferon-stimulated genes identifies a novel negative regulator of the cellular antiviral response.the type i interferon (ifn) signaling pathway restricts infection of many divergent families of rna and dna viruses by inducing hundreds of ifn-stimulated genes (isgs), some of which have direct antiviral activity. we screened 813 short hairpin rna (shrna) constructs targeting 245 human isgs using a flow cytometry approach to identify genes that modulated infection of west nile virus (wnv) in ifn-β-treated human cells. thirty isgs with inhibitory effects against wnv were identified, including se ...201323781071
prenylome profiling reveals s-farnesylation is crucial for membrane targeting and antiviral activity of zap long-isoform.s-prenylation is an important lipid modification that targets proteins to membranes for cell signaling and vesicle trafficking in eukaryotes. as s-prenylated proteins are often key effectors for oncogenesis, congenital disorders, and microbial pathogenesis, robust proteomic methods are still needed to biochemically characterize these lipidated proteins in specific cell types and disease states. here, we report that bioorthogonal proteomics of macrophages with an improved alkyne-isoprenoid chemic ...201323776219
neuro-invasion of chandipura virus mediates pathogenesis in experimentally infected mice.neuro-tropism is a major feature in many viral infections. chandipura virus produces neurological symptoms in naturally infected young children and experimentally infected suckling mice. this study was undertaken to find out the neuro-invasive behaviour of chandipura virus in suckling mice. the suckling mice were infected with the virus via footpad injection. different tissues were collected at 24-h intervals up to 96-h post infection and processed for virus quantification and histological study ...201323826408
recombinant varicella-zoster virus vaccines as platforms for expression of foreign antigens.varicella-zoster virus (vzv) vaccines induce immunity against childhood chickenpox and against shingles in older adults. the safety, efficacy, and widespread use of vzv vaccines suggest that they may also be effective as recombinant vaccines against other infectious diseases that affect the young and the elderly. the generation of recombinant vzv vaccines and their evaluation in animal models are reviewed. the potential advantages and limitations of recombinant vzv vaccines are addressed.201323843791
cytoplasmic rna viruses as potential vehicles for the delivery of therapeutic small rnas.viral vectors have become the best option for the delivery of therapeutic genes in conventional and rna interference-based gene therapies. the current viral vectors for the delivery of small regulatory rnas are based on dna viruses and retroviruses/lentiviruses. cytoplasmic rna viruses have been excluded as viral vectors for rnai therapy because of the nuclear localization of the microprocessor complex and the potential degradation of the viral rna genome during the excision of any virus-encoded ...201323759022
inhibition of human immunodeficiency virus type-1 through autophagy.as an obligatory intracellular pathogen, human immunodeficiency virus type-1 (hiv) is dependent upon its ability to exploit host cell machinery for replication and dissemination, and to circumvent cellular processes that prevent its growth. one such intracellular process is autophagy, a component of the host defense against hiv with roles in innate immune signaling, adaptive immunity and intracellular degradation of hiv. during permissive infection, hiv down-modulates autophagy, promoting its ow ...201323747172
tinkering with translation: protein synthesis in virus-infected cells.viruses are obligate intracellular parasites, and their replication requires host cell functions. although the size, composition, complexity, and functions encoded by their genomes are remarkably diverse, all viruses rely absolutely on the protein synthesis machinery of their host cells. lacking their own translational apparatus, they must recruit cellular ribosomes in order to translate viral mrnas and produce the protein products required for their replication. in addition, there are other con ...201323209131
human papillomavirus infection is inhibited by host autophagy in primary human keratinocytes.human papillomavirus (hpv) infection is severely limited in its natural host, primary human keratinocytes. our data show hpv infectivity in primary keratinocytes is over 100- and 1,000-fold lower than in established keratinocyte cell lines niks and hacat, respectively. here, we show that the basal level of autophagy in primary human foreskin keratinocytes (hfks) is higher than in immortalized keratinocytes, and that hpv16 virions significantly induce autophagy in hfks. interestingly, hpv16 infec ...201323290079
bioluminescent imaging and histopathologic characterization of weev neuroinvasion in outbred cd-1 mice.western equine encephalitis virus (weev; alphavirus) is a mosquito-borne virus that can cause severe encephalitis in humans and equids. previous studies have shown that intranasal infection of outbred cd-1 mice with the weev mcmillan (mcm) strain result in high mortality within 4 days of infection. here in vivo and ex vivo bioluminescence (blm) imaging was applied on mice intranasally infected with a recombinant mcm virus expressing firefly luciferase (fluc) to track viral neuroinvasion by fluc ...201323301074
hypervariable domain of nonstructural protein nsp3 of venezuelan equine encephalitis virus determines cell-specific mode of virus replication.venezuelan equine encephalitis virus (veev) is one of the most pathogenic members of the alphavirus genus in the togaviridae family. this genus is divided into the old world and new world alphaviruses, which demonstrate profound differences in pathogenesis, replication, and virus-host interactions. veev is a representative member of the new world alphaviruses. the biology of this virus is still insufficiently understood, particularly the function of its nonstructural proteins in rna replication ...201323637407
mhc class ii-alpha chain knockout mice support increased viral replication that is independent of their lack of mhc class ii cell surface expression and associated immune function deficiencies.mhcii molecules are heterodimeric cell surface proteins composed of an α and β chain. these molecules are almost exclusively expressed on thymic epithelium and antigen presenting cells (apcs) and play a central role in the development and function of cd4 t cells. various mhc-ii knockout mice have been generated including mhc-iiaα(-/-) (i-aα(-/-)), mhc-iiaβ(-/-) (i-β(-/-)) and the double knockout (i-aαxβ(-/-)). here we report a very striking observation, namely that alphaviruses including the avi ...201323840854
the role of innate versus adaptive immune responses in a mouse model of o'nyong-nyong virus infection.o'nyong-nyong virus (onnv), an alphavirus closely related to chikungunya virus (chikv), has caused three major epidemics in africa since 1959. both onnv and chikv produce similar syndromes with fever, rash, and debilitating arthralgia. to determine the roles of the innate and adaptive immune responses, we infected different knockout mice with two strains of onnv (sg650 and mp30). wild-type, rag1 ko, and ifnγr ko mice showed no signs of illness or viremia. the stat1 ko and a129 mice exhibited 50- ...201323568285
viruses and antiviral immunity in drosophila.viral pathogens present many challenges to organisms, driving the evolution of a myriad of antiviral strategies to combat infections. a wide variety of viruses infect invertebrates, including both natural pathogens that are insect-restricted, and viruses that are transmitted to vertebrates. studies using the powerful tools in the model organism drosophila have expanded our understanding of antiviral defenses against diverse viruses. in this review, we will cover three major areas. first, we will ...201323680639
a fully attenuated recombinant salmonid alphavirus becomes pathogenic through a single amino acid change in the e2 glycoprotein.a recombinant sleeping disease virus (rsdv) was previously shown to be totally attenuated and provide long-term protection in trout (c. moriette, m. leberre, a. lamoureux, t. l. lai, m. brémont, j. virol. 80:4088-4098, 2006). sequence comparison of the rsdv to wild-type genomes exhibited a number of nucleotide changes. in the current study, we demonstrate that the virulent phenotype of sdv was essentially associated with two amino acid changes, v8a and m136t, in the e2 glycoprotein, with the v8a ...201323449806
structural analyses at pseudo atomic resolution of chikungunya virus and antibodies show mechanisms of neutralization.a 5.3 å resolution, cryo-electron microscopy (cryoem) map of chikungunya virus-like particles (vlps) has been interpreted using the previously published crystal structure of the chikungunya e1-e2 glycoprotein heterodimer. the heterodimer structure was divided into domains to obtain a good fit to the cryoem density. differences in the t = 4 quasi-equivalent heterodimer components show their adaptation to different environments. the spikes on the icosahedral 3-fold axes and those in general positi ...201323577234
predictors of chikungunya rheumatism: a prognostic survey ancillary to the telechik cohort study.long-lasting relapsing or lingering rheumatic musculoskeletal pain (rmsp) is the hallmark of chikungunya virus (chikv) rheumatism (chik-r). little is known on their prognostic factors. the aim of this prognostic study was to search the determinants of lingering or relapsing rmsp indicative of chik-r.201323302155
infection of myofibers contributes to increased pathogenicity during infection with an epidemic strain of chikungunya virus.chikungunya virus (chikv) is an alphavirus transmitted by mosquitoes that is known to cause severe arthritis and myositis in affected patients. the ongoing epidemic began in eastern africa in 2004 and then spread to islands of the indian ocean, india, and southeast asia, ultimately afflicting millions. during this outbreak, more severe disease manifestations, including fatalities, have been documented. the reasons for this change in pathogenesis are multifactorial but likely include mutations th ...201324335291
a single-amino-acid polymorphism in chikungunya virus e2 glycoprotein influences glycosaminoglycan utilization.chikungunya virus (chikv) is a reemerging arbovirus responsible for outbreaks of infection throughout asia and africa, causing an acute illness characterized by fever, rash, and polyarthralgia. although chikv infects a broad range of host cells, little is known about how chikv binds and gains access to the target cell interior. in this study, we tested whether glycosaminoglycan (gag) binding is required for efficient chikv replication using chikv vaccine strain 181/25 and clinical isolate sl1564 ...201324371059
evolution of bovine ephemeral fever virus in the australian episystem.bovine ephemeral fever virus (befv) is an arthropod-borne rhabdovirus that causes a debilitating disease of cattle in africa, asia, and australia; however, its global geodynamics are poorly understood. an evolutionary analysis of g gene (envelope glycoprotein) ectodomain sequences of 97 befv isolates collected from australia during 1956 to 2012 revealed that all have a single common ancestor and are phylogenetically distinct from befv sampled in other geographical regions. the age of the austral ...201324227855
intrathecal humoral immunity to encephalitic rna viruses.the nervous system is the target for acute encephalitic viral infections, as well as a reservoir for persisting viruses. intrathecal antibody (ab) synthesis is well documented in humans afflicted by infections associated with neurological complications, as well as the demyelinating disease, multiple sclerosis. this review focuses on the origin, recruitment, maintenance, and biological relevance of ab-secreting cells (asc) found in the central nervous system (cns) following experimental neurotrop ...201323435240
structure and antimicrobial properties of monensin a and its derivatives: summary of the achievements.in this paper structural and microbiological studies on the ionophorous antibiotic monensin a and its derivatives have been collected. monensin a is an ionophore which selectively complexes and transports sodium cation across lipid membranes, and therefore it shows a variety of biological properties. this antibiotic is commonly used as coccidiostat and nonhormonal growth promoter. the paper focuses on both the latest and earlier achievements concerning monensin a antimicrobial activity. the acti ...201323509771
bst-2/tetherin-mediated restriction of chikungunya (chikv) vlp budding is counteracted by chikv non-structural protein 1 (nsp1).chikungunya virus (chikv) is a re-emerging alphavirus transmitted by aedes mosquitoes. infection with chikv elicits a type i interferon response that facilities virus clearance, probably through the action of down-stream effectors such as antiviral ifn-stimulated genes (isgs). bone marrow stromal antigen 2 (bst-2) is an isg shown to restrict hiv-1 replication by preventing the infection of bystander cells by tethering progeny virions on the surface of infected cells. here we show that enrichment ...201323411007
dicer-2 processes diverse viral rna species.rna silencing pathways play critical roles in gene regulation, virus infection, and transposon control. rna interference (rnai) is mediated by small interfering rnas (sirnas), which are liberated from double-stranded (ds)rna precursors by dicer and guide the rna-induced silencing complex (risc) to targets. although principles governing small rna sorting into risc have been uncovered, the spectrum of rna species that can be targeted by dicer proteins, particularly the viral rnas present during an ...201323424633
comparative analysis of the genome sequences and replication profiles of chikungunya virus isolates within the east, central and south african (ecsa) lineage.a comparative analysis of the genomic and replication profiles of different geographical chikungunya virus (chikv) isolates of the east, central and south african (ecsa) lineage was performed.201323721429
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