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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
identical strength of the t cell responses against e2, nsp1 and capsid chikv proteins in recovered and chronic patients after the epidemics of 2005-2006 in la reunion island.to characterize the immunity developed by patients infected by chikungunya virus (chikv), we studied the intensity and specificity of chikv-specific t cells mediated responses in chronic and recovered patients at 12 to 24 months post-infection. t cells were challenged in vitro against chikv synthetic peptides covering the length of three viral proteins, capsid, e2 and nsp1 proteins as well as all inactivated virus particles. cytokine production was assessed by elispot and intracellular labeling. ...201324376836
rubella virus capsid protein structure and its role in virus assembly and infection.rubella virus (rv) is a leading cause of birth defects due to infectious agents. when contracted during pregnancy, rv infection leads to severe damage in fetuses. despite its medical importance, compared with the related alphaviruses, very little is known about the structure of rv. the rv capsid protein is an essential structural component of virions as well as a key factor in virus-host interactions. here we describe three crystal structures of the structural domain of the rv capsid protein. th ...201324282305
encapsidation of host-derived factors correlates with enhanced infectivity of sindbis virus.the genus alphavirus consists of a group of enveloped, single-stranded rna viruses, many of which are transmitted by arthropods to a wide range of vertebrate host species. here we report that sindbis virus (sinv) produced from a representative mammalian cell line consists of at least two unique particle subpopulations, separable on the basis of virion density. in contrast, mosquito-derived sinv consists of a homogeneous population of particles. our findings indicate that the denser particle subp ...201324006438
identification of novel compounds inhibiting chikungunya virus-induced cell death by high throughput screening of a kinase inhibitor library.chikungunya virus (chikv) is a mosquito-borne arthrogenic alphavirus that causes acute febrile illness in humans accompanied by joint pains and in many cases, persistent arthralgia lasting weeks to years. the re-emergence of chikv has resulted in numerous outbreaks in the eastern hemisphere, and threatens to expand in the foreseeable future. unfortunately, no effective treatment is currently available. the present study reports the use of resazurin in a cell-based high-throughput assay, and an i ...201324205414
insect antiviral innate immunity: pathways, effectors, and connections.insects are infected by a wide array of viruses some of which are insect restricted and pathogenic, and some of which are transmitted by biting insects to vertebrates. the medical and economic importance of these viruses heightens the need to understand the interaction between the infecting pathogen and the insect immune system in order to develop transmission interventions. the interaction of the virus with the insect host innate immune system plays a critical role in the outcome of infection. ...201324120681
the transmembrane domain and acidic lipid flip-flop regulates voltage-dependent fusion mediated by class ii and iii viral proteins.voltage dependence of fusion induced by class ii and class iii viral fusion proteins was investigated. class ii proteins from ross river and sindbus virus and a mutant class iii protein from epstein barr virus were found to induce cell-cell fusion that is voltage dependent. combined with previous studies, in all, four class ii and two class iii protein have now been shown to exhibit voltage-dependent fusion, demonstrating that this is probably a general phenomenon for these two classes of viral ...201324124539
the antiviral activities of isg15.post-translational protein modification is an important strategy for the regulation of the cell proteome independent of the need for new gene expression. ubiquitin and ubiquitin-like modifiers mediate the regulation of protein levels, signaling pathways, vesicular trafficking, and many other cellular processes through their covalent conjugation to proteins. interferon stimulated gene 15 (isg15) is a ubiquitin-like modifier induced by type i interferon. in addition to conjugating to potentially h ...201324095857
induction of cytopathogenicity in human glioblastoma cells by chikungunya virus.chikungunya virus (chikv), an arthritogenic old-world alphavirus, has been implicated in the central nervous system (cns) infection in infants and elderly patients. astrocytes are the major immune cells of the brain parenchyma that mediate inflammation. in the present study we found that a local isolate of chikv infect and activate u-87 mg cells, a glioblastoma cell line of human astrocyte origin. the infection kinetics were similar in infected u-87 mg cells and the human embryo kidney (hek293) ...201324086645
the c-terminal domain of chikungunya virus nsp2 independently governs viral rna replication, cytopathicity, and inhibition of interferon signaling.alphavirus nonstructural protein 2 (nsp2) has pivotal roles in viral rna replication, host cell shutoff, and inhibition of antiviral responses. mutations that individually rendered other alphaviruses noncytopathic were introduced into chikungunya virus nsp2. results show that (i) nsp2 mutation p718s only in combination with kr649aa or adaptive mutation d711g allowed noncytopathic replicon rna replication, (ii) prohibiting nsp2 nuclear localization abrogates inhibition of antiviral interferon-ind ...201323864632
multi-gene detection and identification of mosquito-borne rna viruses using an oligonucleotide microarray.arthropod-borne viruses are important emerging pathogens world-wide. viruses transmitted by mosquitoes, such as dengue, yellow fever, and japanese encephalitis viruses, infect hundreds of millions of people and animals each year. global surveillance of these viruses in mosquito vectors using molecular based assays is critical for prevention and control of the associated diseases. here, we report an oligonucleotide dna microarray design, termed arbochip5.1, for multi-gene detection and identifica ...201323967358
bed bugs and infectious disease: a case for the arboviruses. 201323966852
methotrexate treatment causes early onset of disease in a mouse model of ross river virus-induced inflammatory disease through increased monocyte production.part of the togaviridae family, alphaviruses, including chikungunya virus (chikv), sindbis virus (sinv) and ross river virus (rrv), are able to cause significant inflammatory pathologies ranging from arthritis to encephalitis. following symptomatic infection with arthritis-associated alphaviruses, patients often experience severe joint pain, affecting distal and small joints, which can last six months or longer. recently, methotrexate (mtx), a disease modifying anti-rheumatic drug (dmard), was u ...201323951095
point mutations in the paramyxovirus f protein that enhance fusion activity shift the mechanism of complement-mediated virus neutralization.parainfluenza virus 5 (piv5) activates and is neutralized by the alternative pathway (ap) in normal human serum (nhs) but not by heat-inactivated (hi) serum. we have tested the relationship between the fusion activity within the piv5 f protein, the activation of complement pathways, and subsequent complement-mediated virus neutralization. recombinant piv5 viruses with enhanced fusion activity were generated by introducing point mutations in the f fusogenic peptide (g3a) or at a distal site near ...201323785199
role of the phosphatidylserine receptor tim-1 in enveloped-virus entry.the cell surface receptor t cell immunoglobulin mucin domain 1 (tim-1) dramatically enhances filovirus infection of epithelial cells. here, we showed that key phosphatidylserine (ptdser) binding residues of the tim-1 igv domain are critical for ebola virus (ebov) entry through direct interaction with ptdser on the viral envelope. ptdser liposomes but not phosphatidylcholine liposomes competed with tim-1 for ebov pseudovirion binding and transduction. further, annexin v (anxv) substituted for the ...201323698310
functional characterization of the alphavirus tf protein.alphavirus dogma has long dictated the production of a discrete set of structural proteins during infection of a cell: capsid, pe2, 6k, and e1. however, bioinformatic analyses of alphavirus genomes (a. e. firth, b. y. chung, m. n. fleeton, and j. f. atkins, virol. j. 5:108, 2008) suggested that a ribosomal frameshifting event occurs during translation of the alphavirus structural polyprotein. specifically, a frameshift event is suggested to occur during translation of the 6k gene, yielding produ ...201323720714
inhibition of hepatitis b virus replication by the host zinc finger antiviral protein.the zinc finger antiviral protein (zap) is a mammalian host restriction factor that inhibits the replication of a variety of rna viruses, including retroviruses, alphaviruses and filoviruses, through interaction with the zap-responsive elements (zre) in viral rna, and recruiting the exosome to degrade rna substrate. hepatitis b virus (hbv) is a pararetrovirus that replicates its genomic dna via reverse transcription of a viral pregenomic (pg) rna precursor. here, we demonstrate that the two isof ...201323853601
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
imaging of the alphavirus capsid protein during virus replication.alphaviruses are enveloped viruses with highly organized structures. the nucleocapsid (nc) core contains a capsid protein lattice enclosing the plus-sense rna genome, and it is surrounded by a lipid bilayer containing a lattice of the e1 and e2 envelope glycoproteins. capsid protein is synthesized in the cytoplasm and particle budding occurs at the plasma membrane (pm), but the traffic and assembly of viral components and the exit of virions from host cells are not well understood. to visualize ...201323785213
magnetic fractionation and proteomic dissection of cellular organelles occupied by the late replication complexes of semliki forest virus.alphavirus replicase complexes are initially formed at the plasma membrane and are subsequently internalized by endocytosis. during the late stages of infection, viral replication organelles are represented by large cytopathic vacuoles, where replicase complexes bind to membranes of endolysosomal origin. in addition to viral components, these organelles harbor an unknown number of host proteins. in this study, a fraction of modified lysosomes carrying functionally intact replicase complexes was ...201323864636
presentation overrides specificity: probing the plasticity of alphaviral proteolytic activity through mutational analysis.semliki forest virus (genus alphavirus) is an important model for studying regulated nonstructural (ns) polyprotein processing. in this study, we evaluated the strictness of the previously outlined cleavage rules, accounting for the timing and outcome of each of three cleavages within the ns polyprotein p1234, and assessed the significance of residues p6 to p4 within the cleavage sites using an alanine scanning approach. the processing of the 1/2 and 3/4 sites was most strongly affected followin ...201323864614
a compact viral processing proteinase/ubiquitin hydrolase from the otu family.turnip yellow mosaic virus (tymv)--a member of the alphavirus-like supergroup of viruses--serves as a model system for positive-stranded rna virus membrane-bound replication. tymv encodes a precursor replication polyprotein that is processed by the endoproteolytic activity of its internal cysteine proteinase domain (pro). we recently reported that pro is actually a multifunctional enzyme with a specific ubiquitin hydrolase (dub) activity that contributes to viral infectivity. here, we report the ...201323966860
template rna length determines the size of replication complex spherules for semliki forest virus.the replication complexes of positive-strand rna viruses are always associated with cellular membranes. the morphology of the replication-associated membranes is altered in different ways in different viral systems, but many viruses induce small membrane invaginations known as spherules as their replication sites. we show here that for semliki forest virus (sfv), an alphavirus, the size of the spherules is tightly connected with the length of the replicating rna template. cells with different mo ...201323760239
characterization of an early-stage fusion intermediate of sindbis virus using cryoelectron microscopy.the sequential steps in the alphavirus membrane fusion pathway have been postulated based on the prefusion and postfusion crystal structures of the viral fusion protein e1 in conjunction with biochemical studies. however, the molecular structures of the hypothesized fusion intermediates have remained obscure due to difficulties inherent in the dynamic nature of the process. we developed an experimental system that uses liposomes as the target membrane to capture sindbis virus, a prototypical alp ...201323898184
virus replicon particle based chikungunya virus neutralization assay using gaussia luciferase as readout.chikungunya virus (chikv) has been responsible for large epidemic outbreaks causing fever, headache, rash and severe arthralgia. so far, no specific treatment or vaccine is available. as nucleic acid amplification can only be used during the viremic phase of the disease, serological tests like neutralization assays are necessary for chikv diagnosis and for determination of the immune status of a patient. furthermore, neutralization assays represent a useful tool to validate the efficacy of poten ...201323855906
knockdown of pirna pathway proteins results in enhanced semliki forest virus production in mosquito cells.the exogenous sirna pathway is important in restricting arbovirus infection in mosquitoes. less is known about the role of the piwi-interacting rna pathway, or pirna pathway, in antiviral responses. viral pirna-like molecules have recently been described following infection of mosquitoes and derived cell lines with several arboviruses. the pirna pathway has thus been suggested to function as an additional small rna-mediated antiviral response to the known infection-induced sirna response. here w ...201323559478
cross-inhibition of chikungunya virus fusion and infection by alphavirus e1 domain iii proteins.alphaviruses are small enveloped rna viruses that include important emerging human pathogens, such as chikungunya virus (chikv). these viruses infect cells via a low-ph-triggered membrane fusion reaction, making this step a potential target for antiviral therapies. the e1 fusion protein inserts into the target membrane, trimerizes, and refolds to a hairpin-like conformation in which the combination of e1 domain iii (diii) and the stem region (diii-stem) pack against a core trimer composed of e1 ...201323637415
the amino-terminal domain of alphavirus capsid protein is dispensable for viral particle assembly but regulates rna encapsidation through cooperative functions of its subdomains.venezuelan equine encephalitis virus (veev) is a pathogenic alphavirus, which circulates in the central, south, and north americas, including the united states, and represents a significant public health threat. in recent years, strong progress has been made in understanding the structure of veev virions, but the mechanism of their formation has yet to be investigated. in this study, we analyzed the functions of different capsid-specific domains and its amino-terminal subdomains in viral particl ...201324006447
infectious bronchitis virus generates spherules from zippered endoplasmic reticulum membranes.replication of positive-sense rna viruses is associated with the rearrangement of cellular membranes. previous work on the infection of tissue culture cell lines with the betacoronaviruses mouse hepatitis virus and severe acute respiratory syndrome coronavirus (sars-cov) showed that they generate double-membrane vesicles (dmvs) and convoluted membranes as part of a reticular membrane network. here we describe a detailed study of the membrane rearrangements induced by the avian gammacoronavirus i ...201324149513
control of the rescue and replication of semliki forest virus recombinants by the insertion of mirna target sequences.due to their broad cell- and tissue-tropism, alphavirus-based replication-competent vectors are of particular interest for anti-cancer therapy. these properties may, however, be potentially hazardous unless the virus infection is controlled. while the rna genome of alphaviruses precludes the standard control techniques, host mirnas can be used to down-regulate viral replication. in this study, target sites from ubiquitous mirnas and those of mirnas under-represented in cervical cancer cells were ...201324098728
a fusion-inhibiting peptide against rift valley fever virus inhibits multiple, diverse viruses.for enveloped viruses, fusion of the viral envelope with a cellular membrane is critical for a productive infection to occur. this fusion process is mediated by at least three classes of fusion proteins (class i, ii, and iii) based on the protein sequence and structure. for rift valley fever virus (rvfv), the glycoprotein gc (class ii fusion protein) mediates this fusion event following entry into the endocytic pathway, allowing the viral genome access to the cell cytoplasm. here, we show that p ...201324069485
rig-i and mda-5 detection of viral rna-dependent rna polymerase activity restricts positive-strand rna virus replication.type i interferons (ifn) are important for antiviral responses. melanoma differentiation-associated gene 5 (mda-5) and retinoic acid-induced gene i (rig-i) proteins detect cytosolic double-stranded rna (dsrna) or 5'-triphosphate (5'-ppp) rna and mediate ifn production. cytosolic 5'-ppp rna and dsrna are generated during viral rna replication and transcription by viral rna replicases [rna-dependent rna polymerases (rdrp)]. here, we show that the semliki forest virus (sfv) rna replicase can induce ...201324039580
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
role for subgenomic mrna in host translation inhibition during sindbis virus infection of mammalian cells.sindbis virus subgenomic mrna is efficiently translated in infected vertebrate cells whereas host translation is shut-off. deletions in the 5'utr of the subgenomic mrna were made to investigate its role in viral gene expression. deletion of nucleotides 1-10 and 11-20 caused a small plaque phenotype, reduced levels of subgenomic mrna and structural proteins, and increased expression of nonstructural proteins. whereas deletion 1-10 virus inhibited cellular protein synthesis, deletion 11-20 did so ...201323601784
a key interaction between the alphavirus envelope proteins responsible for initial dimer dissociation during fusion.alphaviruses such as semliki forest virus (sfv) are enveloped viruses whose surface is covered by an organized lattice composed of trimers of e2-e1 heterodimers. the e1 envelope protein, a class ii fusion protein, contains the hydrophobic fusion loop and refolds to drive virus fusion with the endosome membrane. the e2 protein is synthesized as a precursor p62, whose processing by furin primes the heterodimer for dissociation during virus entry. dissociation of the e2-e1 heterodimer is an essenti ...201323325694
statistical analysis of sizes and shapes of virus capsids and their resulting elastic properties.from the analysis of sizes of approximately 130 small icosahedral viruses we find that there is a typical structural capsid protein, having a mean diameter of 5 nm and a mean thickness of 3 nm, with more than two thirds of the analyzed capsid proteins having thicknesses between 2 nm and 4 nm. to investigate whether, in addition to the fairly conserved geometry, capsid proteins show similarities in the way they interact with one another, we examined the shapes of the capsids in detail. we classif ...201323860870
o'nyong nyong virus molecular determinants of unique vector specificity reside in non-structural protein 3.o'nyong nyong virus (onnv) and chikungunya virus (chikv) are two closely related alphaviruses with very different infection patterns in the mosquito, anopheles gambiae. onnv is the only alphavirus transmitted by anopheline mosquitoes, but specific molecular determinants of infection of this unique vector specificity remain unidentified. fifteen distinct chimeric viruses were constructed to evaluate both structural and non-structural regions of the genome and infection patterns were determined th ...201323359824
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
autophagy as an innate immune modulator.autophagy is a fundamental cellular process in eukaryotic cells for maintaining homeostasis by degrading cellular proteins and organelles. recently, the roles of autophagy have been expanded to immune systems, which in turn modulate innate immune responses. more specifically, autophagy acts as a direct effector for protection against pathogens, as well as a modulator of pathogen recognition and downstream signaling in innate immune responses. in addition, autophagy controls autoimmunity and infl ...201323559894
sustained activation of akt elicits mitochondrial dysfunction to block plasmodium falciparum infection in the mosquito host.the overexpression of activated, myristoylated akt in the midgut of female transgenic anopheles stephensi results in resistance to infection with the human malaria parasite plasmodium falciparum but also decreased lifespan. in the present study, the understanding of mitochondria-dependent midgut homeostasis has been expanded to explain this apparent paradox in an insect of major medical importance. given that akt signaling is essential for cell growth and survival, we hypothesized that sustained ...201323468624
acute bdnf treatment upregulates glur1-sap97 and glur2-grip1 interactions: implications for sustained ampa receptor expression.brain-derived neurotrophic factor (bdnf) plays several prominent roles in synaptic plasticity and in learning and memory formation. reduced bdnf levels and altered bdnf signaling have been reported in several brain diseases and behavioral disorders, which also exhibit reduced levels of ampar subunits. bdnf treatment acutely regulates ampa receptor expression and function, including synaptic ampar subunit trafficking, and implicates several well defined signaling molecules that are required to el ...201323460828
immune responses of a native and an invasive bird to buggy creek virus (togaviridae: alphavirus) and its arthropod vector, the swallow bug (oeciacus vicarius).invasive species often display different patterns of parasite burden and virulence compared to their native counterparts. these differences may be the result of variability in host-parasite co-evolutionary relationships, the occurrence of novel host-parasite encounters, or possibly innate differences in physiological responses to infection between invasive and native hosts. here we examine the adaptive, humoral immune responses of a resistant, native bird and a susceptible, invasive bird to an a ...201323460922
the δ2 glutamate receptor gates long-term depression by coordinating interactions between two ampa receptor phosphorylation sites.long-term depression (ltd) commonly affects learning and memory in various brain regions. although cerebellar ltd absolutely requires the δ2 glutamate receptor (glud2) that is expressed in purkinje cells, ltd in other brain regions does not; why and how cerebellar ltd is regulated by glud2 remains unelucidated. here, we show that the activity-dependent phosphorylation of serine 880 (s880) in glua2 ampa receptor subunit, which is an essential step for ampa receptor endocytosis during ltd inductio ...201323431139
metabotropic nmda receptor function is required for β-amyloid-induced synaptic depression.the mechanisms by which β-amyloid (aβ), a peptide fragment believed to contribute to alzheimer's disease, leads to synaptic deficits are not known. here we find that elevated oligomeric aβ requires ion flux-independent function of nmda receptors (nmdars) to produce synaptic depression. aβ activates this metabotropic nmdar function on glun2b-containing nmdars but not on those containing glun2a. furthermore, oligomeric aβ leads to a selective loss of synaptic glun2b responses, effecting a switch i ...201323431156
interferon-induced isg15 pathway: an ongoing virus-host battle.isg15 is an interferon (ifn)-induced ubiquitin-like protein that is conjugated to target proteins via the sequential action of three enzymes that are also induced by ifn. unlike ubiquitin, which is highly conserved, the sequence of isg15 varies between species. isg15 conjugation inhibits many viruses, and free (unconjugated) isg15 can also act as an antiviral protein. in this review, we focus on the antiviral role of isg15 conjugation and on countermeasures employed by several viruses. the count ...201323414970
development of one-step quantitative reverse transcription pcr for the rapid detection of flaviviruses.the genus flavivirus includes several pathogenic agents that cause severe illness in humans. re-emergence of west nile virus in europe and continuous spread of certain flaviviruses such as dengue, yellow fever and japanese encephalitis viruses represent a global danger to public health. therefore, a rapid and accurate molecular method is required for diagnostics and epidemiological surveillance of flaviviruses.201323410000
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
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
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
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
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
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
design of a novel integration-deficient lentivector technology that incorporates genetic and posttranslational elements to target human dendritic cells.as sentinels of the immune system, dendritic cells (dcs) play an essential role in regulating cellular immune responses. one of the main challenges of developing dc-targeted therapies includes the delivery of antigen to dcs in order to promote the activation of antigen-specific effector cd8 t cells. with the goal of creating antigen-directed immunotherapeutics that can be safely administered directly to patients, immune design has developed a platform of novel integration-deficient lentiviral ve ...201324419083
novel treatment with neuroprotective and antiviral properties against a neuroinvasive human respiratory virus.human coronaviruses (hcovs) are recognized respiratory pathogens with neuroinvasive and neurotropic properties in mice and humans. hcov strain oc43 (hcov-oc43) can infect and persist in human neural cells and activate neuroinflammatory and neurodegenerative mechanisms, suggesting that it could be involved in neurological disease of unknown etiology in humans. moreover, we have shown that hcov-oc43 is neurovirulent in susceptible mice, causing encephalitis, and that a viral mutant with a single p ...201324227863
liposome-antigen-nucleic acid complexes protect mice from lethal challenge with western and eastern equine encephalitis viruses.alphaviruses are mosquito-borne viruses that cause significant disease in animals and humans. western equine encephalitis virus (weev) and eastern equine encephalitis virus (eeev), two new world alphaviruses, can cause fatal encephalitis, and eeev is a select agent of concern in biodefense. however, we have no antiviral therapies against alphaviral disease, and current vaccine strategies target only a single alphavirus species. in an effort to develop new tools for a broader response to outbreak ...201324257615
bovine ephemeral fever rhabdovirus α1 protein has viroporin-like properties and binds importin β1 and importin 7.bovine ephemeral fever virus (befv) is an arthropod-borne rhabdovirus that is classified as the type species of the genus ephemerovirus. in addition to the five canonical rhabdovirus structural proteins (n, p, m, g, and l), the large and complex befv genome contains several open reading frames (orfs) between the g and l genes (α1, α2/α3, β, and γ) encoding proteins of unknown function. we show that the 10.5-kda befv α1 protein is expressed in infected cells and, consistent with previous predicti ...201324257609
isg15 is counteracted by vaccinia virus e3 protein and controls the proinflammatory response against viral infection.conjugation of isg15 inhibits replication of several viruses. here, using an expression system for assaying human and mouse isg15 conjugations (isgylations), we have demonstrated that vaccinia virus e3 protein binds and antagonizes human and mouse isg15 modification. to study isgylation importance in poxvirus infection, we used a mouse model that expresses deconjugating proteases. our results indicate that isgylation restricts in vitro replication of the vaccinia virus vvδe3l mutant but unconjug ...201324257616
phosphorylation of initiation factor eif2 in response to stress conditions is mediated by acidic ribosomal p1/p2 proteins in saccharomyces cerevisiae.eukaryotic cells contain an unusually large cytoplasmic pool of p1/p2 phosphoproteins, which form the highly flexible 60s subunit stalk that is required to interact with and activate soluble translation factors. in cells, cytoplasmic p1/p2 proteins are exchanged for ribosome-bound proteins in a process that can modulate ribosome function and translation. here, we analysed different s. cerevisiae stalk mutants grown under stress conditions that result in eif2α phosphorylation. these mutants eithe ...201324391917
small rna analysis in sindbis virus infected human hek293 cells.in contrast to the defence mechanism of rna interference (rnai) in plants and invertebrates, its role in the innate response to virus infection of mammals is a matter of debate. since rnai has a well-established role in controlling infection of the alphavirus sindbis virus (sinv) in insects, we have used this virus to investigate the role of rnai in sinv infection of human cells.201324391886
chemistry and biological activities of flavonoids: an overview.there has been increasing interest in the research on flavonoids from plant sources because of their versatile health benefits reported in various epidemiological studies. since flavonoids are directly associated with human dietary ingredients and health, there is need to evaluate structure and function relationship. the bioavailability, metabolism, and biological activity of flavonoids depend upon the configuration, total number of hydroxyl groups, and substitution of functional groups about th ...201324470791
antiviral autophagy restrictsrift valley fever virus infection and is conserved from flies to mammals.autophagy has been implicated as a component of host defense, but the significance of antimicrobial autophagy in vivo and the mechanism by which it is regulated during infection are poorly defined. here we found that antiviral autophagy was conserved in flies and mammals during infection with rift valley fever virus (rvfv), a mosquito-borne virus that causes disease in humans and livestock. in drosophila, toll-7 limited rvfv replication and mortality through activation of autophagy. rvfv infecti ...201324374193
inhibition of translation by ifit family members is determined by their ability to interact selectively with the 5'-terminal regions of cap0-, cap1- and 5'ppp- mrnas.ribosomal recruitment of cellular mrnas depends on binding of eif4f to the mrna's 5'-terminal 'cap'. the minimal 'cap0' consists of n7-methylguanosine linked to the first nucleotide via a 5'-5' triphosphate (ppp) bridge. cap0 is further modified by 2'-o-methylation of the next two riboses, yielding 'cap1' (m7gpppnmn) and 'cap2' (m7gpppnmnm). however, some viral rnas lack 2'-o-methylation, whereas others contain only ppp- at their 5'-end. interferon-induced proteins with tetratricopeptide repeats ...201324371270
structural basis for the regulatory function of a complex zinc-binding domain in a replicative arterivirus helicase resembling a nonsense-mediated mrna decay helicase.all positive-stranded rna viruses with genomes>∼7 kb encode helicases, which generally are poorly characterized. the core of the nidovirus superfamily 1 helicase (hel1) is associated with a unique n-terminal zinc-binding domain (zbd) that was previously implicated in helicase regulation, genome replication and subgenomic mrna synthesis. the high-resolution structure of the arterivirus helicase (nsp10), alone and in complex with a polynucleotide substrate, now provides first insights into the str ...201324369429
ghrelin triggers the synaptic incorporation of ampa receptors in the hippocampus.ghrelin is a peptide mainly produced by the stomach and released into circulation, affecting energy balance and growth hormone release. these effects are guided largely by the expression of the ghrelin receptor growth hormone secretagogue type 1a (ghs-r1a) in the hypothalamus and pituitary. however, ghs-r1a is expressed in other brain regions, including the hippocampus, where its activation enhances memory retention. herein we explore the molecular mechanism underlying the action of ghrelin on h ...201324367106
mers-cov papain-like protease has deisgylating and deubiquitinating activities.coronaviruses encode papain-like proteases (plpro) that are often multifunctional enzymes with protease activity to process the viral replicase polyprotein and deubiquitinating (dub)/deisgylating activity, which is hypothesized to modify the innate immune response to infection. here, we investigate the predicted dub activity of the plpro domain of the recently described middle east respiratory syndrome coronavirus (mers-cov). we found that expression of mers-cov plpro reduces the levels of ubiqu ...201324503068
subgenomic reporter rna system for detection of alphavirus infection in mosquitoes.current methods for detecting real-time alphavirus (family togaviridae) infection in mosquitoes require the use of recombinant viruses engineered to express a visibly detectable reporter protein. these altered viruses expressing fluorescent proteins, usually from a duplicated viral subgenomic reporter, are effective at marking infection but tend to be attenuated due to the modification of the genome. additionally, field strains of viruses cannot be visualized using this approach unless infectiou ...201324367703
type 1 metabotropic glutamate receptors (mglu1) trigger the gating of glud2 delta glutamate receptors.the orphan glud2 receptor belongs to the ionotropic glutamate receptor family but does not bind glutamate. ligand-gated glud2 currents have never been evidenced, and whether glud2 operates as an ion channel has been a long-standing question. here, we show that glud2 gating is triggered by type 1 metabotropic glutamate receptors, both in a heterologous expression system and in purkinje cells. thus, glud2 is not only an adhesion molecule at synapses but also works as a channel. this gating mechani ...201324357660
the influence of viral rna secondary structure on interactions with innate host cell defences.rna viruses infecting vertebrates differ fundamentally in their ability to establish persistent infections with markedly different patterns of transmission, disease mechanisms and evolutionary relationships with their hosts. although interactions with host innate and adaptive responses are complex and persistence mechanisms likely multi-factorial, we previously observed associations between bioinformatically predicted rna secondary formation in genomes of positive-stranded rna viruses with their ...201324335283
gene therapy strategies for hiv/aids: preclinical modeling in humanized mice.in the absence of an effective vaccine and lack of a complete cure, gene therapy approaches to control hiv infection offer feasible alternatives. due to the chronic nature of infection, a wide window of opportunity exists to gene modify the hiv susceptible cells that continuously arise from the bone marrow source. to evaluate promising gene therapy approaches that employ various anti-hiv therapeutic molecules, an ideal animal model is necessary to generate important efficacy and preclinical data ...201324351796
genome-wide rnai screen identifies sec61a and vcp as conserved regulators of sindbis virus entry.alphaviruses are a large class of insect-borne human pathogens and little is known about the host-factor requirements for infection. to identify such factors, we performed a genome-wide rnai screen using model drosophila cells and validated 94 genes that impacted infection of sindbis virus (sinv), the prototypical alphavirus. we identified a conserved role for sec61a and valosin-containing protein (vcp) in facilitating sinv entry in insects and mammals. sec61a and vcp selectively regulate traffi ...201324332855
exploring early stages of the chemical unfolding of proteins at the proteome scale.after decades of using urea as denaturant, the kinetic role of this molecule in the unfolding process is still undefined: does urea actively induce protein unfolding or passively stabilize the unfolded state? by analyzing a set of 30 proteins (representative of all native folds) through extensive molecular dynamics simulations in denaturant (using a range of force-fields), we derived robust rules for urea unfolding that are valid at the proteome level. irrespective of the protein fold, presence ...201324348236
cytoplasmic viruses: rage against the (cellular rna decay) machine. 201324339774
initial evidence on differences among enterovirus 71, coxsackievirus a16 and coxsackievirus b4 in binding to cell surface heparan sulphate.cell surface heparan sulphate (hs) mediates infection for many viruses from diverse families. we demonstrated significant antiviral potencies for a number of hs mimetics against a cloned strain of enterovirus 71 (ev71) in a previous study. thus, the involvement of hs in mediating viral infection of isolates of human enteroviruses was investigated in vero and human neural cells in the present work. in both cell lines, heparin and pentosan polysulphate significantly inhibited both infection and at ...201325674594
glun3a expression restricts spine maturation via inhibition of git1/rac1 signaling.nmda-type glutamate receptors (nmdars) guide the activity-dependent remodeling of excitatory synapses and associated dendritic spines during critical periods of postnatal brain development. whereas mature nmdars composed of glun1 and glun2 subunits mediate synapse plasticity and promote spine growth and stabilization, juvenile nmdars containing glun3a subunits are thought to inhibit these processes via yet unknown mechanisms. here, we report that glun3a binds g protein-coupled receptor kinase-in ...201324297929
emerging roles for immunomodulatory functions of free isg15.type i interferons (ifns) exert their effects through the induction of hundreds of ifn-stimulated genes (isgs), many of which function by inhibiting viral replication and modulating immune responses. isg15, a di-ubiquitin-like protein, is one of the most abundantly induced isgs and is critical for control of certain viral and bacterial infections. like ubiquitin, isg15 is covalently conjugated to target proteins. in addition, free unconjugated isg15 is present both intra- and extracellularly. al ...201324010825
evasion of superinfection exclusion and elimination of primary viral rna by an adapted strain of hepatitis c virus.cells that are productively infected by hepatitis c virus (hcv) are refractory to a second infection by hcv via a block in viral replication known as superinfection exclusion. the block occurs at a postentry step and likely involves translation or replication of the secondary viral rna, but the mechanism is largely unknown. to characterize hcv superinfection exclusion, we selected for an hcv variant that could overcome the block. we produced a high-titer hc-j6/jfh1 (jc1) viral genome with a fluo ...201324089557
highly sensitive real-time in vivo imaging of an influenza reporter virus reveals dynamics of replication and spread.the continual public health threat posed by the emergence of novel influenza viruses necessitates the ability to rapidly monitor infection and spread in experimental systems. to analyze real-time infection dynamics, we have created a replication-competent influenza reporter virus suitable for in vivo imaging. the reporter virus encodes the small and bright nanoluc luciferase whose activity serves as an extremely sensitive readout of viral infection. this virus stably maintains the reporter const ...201324089552
apoptosis induction influences reovirus replication and virulence in newborn mice.apoptosis is a type of controlled cell death that is essential for development and tissue homeostasis. it also serves as a robust host response against infection by many viruses. the capacity of neurotropic viruses to induce apoptosis strongly correlates with virulence. however, the precise function of apoptosis in viral infection is not well understood. reovirus is a neurotropic virus that induces apoptosis in a variety of cell types, including central nervous system neurons, leading to fatal e ...201324067960
pan-viral specificity of ifn-induced genes reveals new roles for cgas in innate immunity.the type i interferon (ifn) response protects cells from viral infection by inducing hundreds of interferon-stimulated genes (isgs), some of which encode direct antiviral effectors. recent screening studies have begun to catalogue isgs with antiviral activity against several rna and dna viruses. however, antiviral isg specificity across multiple distinct classes of viruses remains largely unexplored. here we used an ectopic expression assay to screen a library of more than 350 human isgs for eff ...201324284630
rim1α sumoylation is required for fast synaptic vesicle exocytosis.the rapid, activity-dependent quantal presynaptic release of neurotransmitter is vital for brain function. the complex process of vesicle priming, fusion, and retrieval is very precisely controlled and requires the spatiotemporal coordination of multiple protein-protein interactions. here, we show that posttranslational modification of the active zone protein rab3-interacting molecule 1α (rim1α) by the small ubiquitin-like modifier 1 (sumo-1) functions as a molecular switch to direct these inter ...201324290762
full inactivation of human influenza virus by high hydrostatic pressure preserves virus structure and membrane fusion while conferring protection to mice against infection.whole inactivated vaccines (wivs) possess greater immunogenicity than split or subunit vaccines, and recent studies have demonstrated that wivs with preserved fusogenic activity are more protective than non-fusogenic wivs. in this work, we describe the inactivation of human influenza virus x-31 by high hydrostatic pressure (hhp) and analyze the effects on the structure by spectroscopic measurements, light scattering, and electron microscopy. we also investigated the effects of hhp on the glycopr ...201324282553
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