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genome-wide rnai screen identifies novel host proteins required for alphavirus entry.the enveloped alphaviruses include important and emerging human pathogens such as chikungunya virus and eastern equine encephalitis virus. alphaviruses enter cells by clathrin-mediated endocytosis, and exit by budding from the plasma membrane. while there has been considerable progress in defining the structure and function of the viral proteins, relatively little is known about the host factors involved in alphavirus infection. we used a genome-wide sirna screen to identify host factors that pr ...201324367265
zoonotic encephalitides caused by arboviruses: transmission and epidemiology of alphaviruses and flaviviruses.in this review, we mainly focus on zoonotic encephalitides caused by arthropod-borne viruses (arboviruses) of the families flaviviridae (genus flavivirus) and togaviridae (genus alphavirus) that are important in both humans and domestic animals. specifically, we will focus on alphaviruses (eastern equine encephalitis virus, western equine encephalitis virus, venezuelan equine encephalitis virus) and flaviviruses (japanese encephalitis virus and west nile virus). most of these viruses were origin ...201324427764
surveillance for arboviral zoonoses in new zealand birds.given the significant burden that emerging infectious diseases place on global economies and public health, the monitoring and mitigation of, and early response to, potential infectious diseases are of the highest priority. the objective of this study was to survey for known and other potential arboviral zoonoses in multiple bird species at four locations in new zealand.201324478919
a genome-wide analysis of rna pseudoknots that stimulate efficient -1 ribosomal frameshifting or readthrough in animal viruses.programmed -1 ribosomal frameshifting (prf) and stop codon readthrough are two translational recoding mechanisms utilized by some rna viruses to express their structural and enzymatic proteins at a defined ratio. efficient recoding usually requires an rna pseudoknot located several nucleotides downstream from the recoding site. to assess the strategic importance of the recoding pseudoknots, we have carried out a large scale genome-wide analysis in which we used an in-house developed program to d ...201324298557
enhanced arbovirus surveillance with deep sequencing: identification of novel rhabdoviruses and bunyaviruses in australian mosquitoes.viral metagenomics characterizes known and identifies unknown viruses based on sequence similarities to any previously sequenced viral genomes. a metagenomics approach was used to identify virus sequences in australian mosquitoes causing cytopathic effects in inoculated mammalian cell cultures. sequence comparisons revealed strains of liao ning virus (reovirus, seadornavirus), previously detected only in china, livestock-infecting stretch lagoon virus (reovirus, orbivirus), two novel dimarhabdov ...201324314645
the role of e3 in ph protection during alphavirus assembly and exit.alphaviruses are small enveloped viruses whose surface is covered by spikes composed of trimers of e2/e1 glycoprotein heterodimers. during virus entry, the e2/e1 dimer dissociates within the acidic endosomal environment, freeing the e1 protein to mediate fusion of the viral and endosome membranes. e2 is synthesized as a precursor, p62, which is cleaved by furin in the late secretory pathway to produce mature e2 and a small peripheral glycoprotein, e3. the immature p62/e1 dimer is acid resistant, ...201323864626
molecular mechanisms involved in the pathogenesis of alphavirus-induced arthritis.arthritogenic alphaviruses, including ross river virus (rrv), chikungunya virus (chikv), sindbis virus (sinv), mayaro virus (mayv), o'nyong-nyong virus (onnv), and barmah forest virus (bfv), cause incapacitating and long lasting articular disease/myalgia. outbreaks of viral arthritis and the global distribution of these diseases point to the emergence of arthritogenic alphaviruses as an important public health problem. this review discusses the molecular mechanisms involved in alphavirus-induced ...201324069610
chikungunya virus capsid protein contains nuclear import and export signals.chikungunya virus (chikv) is an alphavirus of the togaviridae family. after autoproteolytic cleavage, the chikv capsid protein (cp) is involved in rna binding and assembly of the viral particle. the monomeric cp is approximately 30 kda in size and is small enough for passive transport through nuclear pores. some alphaviruses are found to harbor nuclear localization signals (nls) and transport of these proteins between cellular compartments was shown to be energy dependent. the active nuclear imp ...201323984714
dendritic cell immunoreceptor regulates chikungunya virus pathogenesis in mice.chikungunya virus (chikv) is a mosquito-borne alphavirus responsible for recent epidemic outbreaks of debilitating disease in humans. alphaviruses are known to interact with members of the c-type lectin receptor family of pattern recognition proteins, and given that the dendritic cell immunoreceptor (dcir) is known to act as a negative regulator of the host inflammatory response and has previously been associated with rheumatoid arthritis, we evaluated dcir's role in response to chikv infection. ...201323487448
a tyrosine-to-histidine switch at position 18 of the ross river virus e2 glycoprotein is a determinant of virus fitness in disparate hosts.arthritogenic alphaviruses are human pathogens maintained in nature through alternating replication in vertebrates and mosquitoes. using chimeric viruses, we previously reported that replacement of the pe2 coding region of the t48 strain of ross river virus (rrv-t48) with that from the attenuated dc5692 strain, which differ by 7 amino acids, resulted in an attenuated disease phenotype in a mouse model of rrv-induced rheumatic disease. here, we demonstrate that introduction of one of these amino ...201323514884
comprehensive mapping of common immunodominant epitopes in the eastern equine encephalitis virus e2 protein recognized by avian antibody responses.eastern equine encephalitis virus (eeev) is a mosquito-borne virus that can cause both human and equine encephalitis with high case fatality rates. eeev can also be widespread among birds, including pheasants, ostriches, emu, turkeys, whooping cranes and chickens. the e2 protein of eeev and other alphaviruses is an important immunogenic protein that elicits antibodies of diagnostic value. while many therapeutic and diagnostic applications of e2 protein-specific antibodies have been reported, the ...201323922704
antiviral type i and type iii interferon responses in the central nervous system.the central nervous system (cns) harbors highly differentiated cells, such as neurons that are essential to coordinate the functions of complex organisms. this organ is partly protected by the blood-brain barrier (bbb) from toxic substances and pathogens carried in the bloodstream. yet, neurotropic viruses can reach the cns either by crossing the bbb after viremia, or by exploiting motile infected cells as trojan horses, or by using axonal transport. type i and type iii interferons (ifns) are cy ...201323503326
a chimeric sindbis-based vaccine protects cynomolgus macaques against a lethal aerosol challenge of eastern equine encephalitis virus.eastern equine encephalitis virus (eeev) is a mosquito-borne alphavirus that causes sporadic, often fatal disease outbreaks in humans and equids, and is also a biological threat agent. two chimeric vaccine candidates were constructed using a cdna clone with a sindbis virus (sinv) backbone and structural protein genes from either a north (sin/naeeev) or south american (sin/saeeev) strain of eeev. the vaccine candidates were tested in a nonhuman primate (nhp) model of eastern equine encephalitis ( ...201323333212
the drosophila imd pathway in the activation of the humoral immune response.the imd pathway signaling plays a pivotal role in the drosophila defense against bacteria. during the last two decades, significant progress has been made in identifying the components and deciphering the molecular mechanisms underlying this pathway, including the means of bacterial sensing and signal transduction. while these findings have contributed to the understanding of the immune signaling in insects, they have also provided new insights in studying the mammalian nf-κb signaling pathways. ...201323721820
virus-induced cd8+ t cells accelerate the onset of experimental autoimmune encephalomyelitis: implications for how viral infections might trigger multiple sclerosis exacerbations.viral infections can exacerbate multiple sclerosis (ms) through poorly defined mechanisms. we developed an experimental system whereby infection with an asymptomatic neurotropic alphavirus caused a transient acceleration of experimental autoimmune encephalomyelitis (eae) without altering the expansion or differentiation of autoreactive cd4+ t cells. instead, this effect on the clinical course of eae depended on cd8+ t cells that neither participate in viral clearance nor induce neuropathology in ...201323602715
anti-infective properties of epigallocatechin-3-gallate (egcg), a component of green tea.the consumption of green tea (camellia sinensis) has been shown to have many physiological and pharmacological health benefits. in the past two decades several studies have reported that epigallocatechin-3-gallate (egcg), the main constituent of green tea, has anti-infective properties. antiviral activities of egcg with different modes of action have been demonstrated on diverse families of viruses, such as retroviridae, orthomyxoviridae and flaviviridae and include important human pathogens lik ...201323072320
targeting antigens to dendritic cell receptors for vaccine development.dendritic cells (dcs) are highly specialized antigen presenting cells of the immune system which play a key role in regulating immune responses. depending on the method of antigen delivery, dcs stimulate immune responses or induce tolerance. as a consequence of the dual function of dcs, dcs are studied in the context of immunotherapy for both cancer and autoimmune diseases. in vaccine development, a major aim is to induce strong, specific t-cell responses. this is achieved by targeting antigen t ...201324228179
the role of b cells and humoral immunity in mycobacterium tuberculosis infection.tuberculosis (tb) remains a serious threat to public health, causing 2 million deaths annually world-wide. the control of tb has been hindered by the requirement of long duration of treatment involving multiple chemotherapeutic agents, the increased susceptibility to mycobacterium tuberculosis infection in the hiv-infected population, and the development of multi-drug resistant and extensively resistant strains of tubercle bacilli. an efficacious and cost-efficient way to control tb is the devel ...201323468112
intracellular pathogen detection by rig-i-like receptors.the rig-i-like receptors (rlrs) rig-i, mda5, and lgp2 trigger innate immune responses against viral infections that serve to limit virus replication and to stimulate adaptive immunity. rlrs are cytosolic sensors for virus-derived rna and thus responsible for intracellular immune surveillance against infection. rlr signaling requires the adapter protein mavs to induce type i interferon, interferon-stimulated genes, and proinflammatory cytokines. this review focuses on the molecular and cell biolo ...201323611287
diagnosis of barmah forest virus infection by a nested real-time sybr green rt-pcr assay.barmah forest virus (bfv) is a mosquito borne (+) ssrna alphavirus found only in australia. it causes rash, myalgia and arthralgia in humans and is usually diagnosed serologically. we developed a real-time pcr assay to detect bfv in an effort to improve diagnosis early in the course of infection. the limit of detection was 16 genome equivalents with a specificity of 100%. fifty five serum samples from bfv-infected patients were tested by the pcr. 52 of 53 antibody-positive samples were pcr negat ...201323935816
therapeutic targeting of autophagy in disease: biology and pharmacology.autophagy, a process of self-digestion of the cytoplasm and organelles through which cellular components are recycled for reuse or energy production, is an evolutionarily conserved response to metabolic stress found in eukaryotes from yeast to mammals. it is noteworthy that autophagy is also associated with various pathophysiologic conditions in which this cellular process plays either a cytoprotective or cytopathic role in response to a variety of stresses such as metabolic, inflammatory, neuro ...201323943849
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
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
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
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
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
macroautophagy--friend or foe of viral replication? 201323661081
mosquito-borne arbovirus surveillance at selected sites in diverse ecological zones of kenya; 2007 - 2012.increased frequency of arbovirus outbreaks in east africa necessitated the determination of distribution of risk by entomologic arbovirus surveillance. a systematic vector surveillance programme spanning 5 years and covering 11 sites representing seven of the eight provinces in kenya and located in diverse ecological zones was carried out.201323663381
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
beclin 1 and nuclear factor-κbp65 are upregulated in hepatocellular carcinoma.there are no sensitive and specific biomarkers that aid in the clinical diagnosis and prognosis of hepatocellular carcinoma (hcc). the aim of the present study was to determine the mrna and protein expression levels of beclin 1 (becn1) and nuclear factor-κb (nf-κb)p65 in patients with hcc, to evaluate their value as potential diagnostic and prognostic biomarkers. immunohistochemistry and in situ hybridization were used to detect the expression of hepatic becn1 and nf-kbp65 in patients with hcc, ...201323833647
isg15: leading a double life as a secreted molecule.isg15 is a well-known intracellular ubiquitin-like molecule involved in isgylation. however, a recent study has revived the notion first put forward two decades ago that isg15 is also a secreted molecule. human neutrophils, monocytes and lymphocytes can release isg15, even though this protein has no detectable signal peptide sequence. isg15 has also been found in the secretory granules of granulocytes. the mechanism underlying isg15 secretion is unknown. secreted isg15 acts on at least t and nat ...201323579383
striatal neurones have a specific ability to respond to phasic dopamine release.the camp/protein kinase a (pka) signalling cascade is ubiquitous, and each step in this cascade involves enzymes that are expressed in multiple isoforms. we investigated the effects of this diversity on the integration of the pathway in the target cell by comparing prefrontal cortical neurones with striatal neurones which express a very specific set of signalling proteins. the prefrontal cortex and striatum both receive dopaminergic inputs and we analysed the dynamics of the camp/pka signal trig ...201323551948
regulation of stress granules and p-bodies during rna virus infection.rna granules are structures within cells that play major roles in gene expression and homeostasis. two principle kinds of rna granules are conserved from yeast to mammals: stress granules (sgs), which contain stalled translation initiation complexes, and processing bodies (p-bodies, pbs), which are enriched with factors involved in rna turnover. since rna granules are associated with silenced transcripts, viruses subvert rna granule function for replicative advantages. this review, focusing on r ...201323554219
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
interferon-stimulated poly(adp-ribose) polymerases are potent inhibitors of cellular translation and virus replication.the innate immune response is the first line of defense against most viral infections. its activation promotes cell signaling, which reduces virus replication in infected cells and leads to induction of the antiviral state in yet-uninfected cells. this inhibition of virus replication is a result of the activation of a very broad spectrum of specific cellular genes, with each of their products usually making a small but detectable contribution to the overall antiviral state. the lack of a strong, ...201324335297
the role of innate immunity in conditioning mosquito susceptibility to west nile virus.arthropod-borne viruses (arboviruses) represent an emerging threat to human and livestock health globally. in particular, those transmitted by mosquitoes present the greatest challenges to disease control efforts. an understanding of the molecular basis for mosquito innate immunity to arbovirus infection is therefore critical to investigations regarding arbovirus evolution, virus-vector ecology, and mosquito vector competence. in this review, we discuss the current state of understanding regardi ...201324351797
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
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