Publications

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down-regulation of p21-activated serine/threonine kinase 1 is involved in loss of mesencephalic dopamine neurons.although the roles of p21-activated serine/threonine kinase 1 (pak1) have been reported in some neurodegenerative diseases, details regarding neurodegeneration are still limited. hence, we tried to determine the role of pak1 and molecular mechanisms of neuronal death involved in neurodegeneration.201627121078
the modulation of apoptotic pathways by gammaherpesviruses.apoptosis or programmed cell death is a tightly regulated process fundamental for cellular development and elimination of damaged or infected cells during the maintenance of cellular homeostasis. it is also an important cellular defense mechanism against viral invasion. in many instances, abnormal regulation of apoptosis has been associated with a number of diseases, including cancer development. following infection of host cells, persistent and oncogenic viruses such as the members of the gamma ...201627199919
the role of climatic and density dependent factors in shaping mosquito population dynamics: the case of culex pipiens in northwestern italy.culex pipiens mosquito is a species widely spread across europe and represents a competent vector for many arboviruses such as west nile virus (wnv), which has been recently circulating in many european countries, causing hundreds of human cases. in order to identify the main determinants of the high heterogeneity in cx. pipiens abundance observed in piedmont region (northwestern italy) among different seasons, we developed a density-dependent stochastic model that takes explicitly into account ...201627105065
infection pattern and transmission potential of chikungunya virus in two new world laboratory-adapted aedes aegypti strains.chikungunya virus (chikv) is an emerging mosquito-borne virus belonging to the togaviridae, which is transmitted to humans by aedes aegypti and ae. albopictus. we describe the infection pattern of chikv in two new world ae. aegypti strains, hwe and orl. both mosquito strains were susceptible to the virus but showed different infection patterns in midguts and salivary glands. even though acquisition of a bloodmeal showed moderate levels of apoptosis in midgut tissue, there was no obvious addition ...201627102548
pilot longitudinal mosquito surveillance study in the danube delta biosphere reserve and the first reports of anopheles algeriensis theobald, 1903 and aedes hungaricus mihályi, 1955 for romania.mosquito-borne viruses (moboviruses) are of growing importance in many countries of europe. in romania and especially in the danube delta biosphere reserve (ddbr), mosquito and mobovirus surveillance are not performed on a regular basis. however, this type of study is crucially needed to evaluate the risk of pathogen transmission, to understand the ecology of emerging moboviruses, or to plan vector control programmes.201627066827
ecological characterization and molecular differentiation of culex pipiens complex taxa and culex torrentium in eastern austria.culex pipiens complex taxa differ in behaviour, ecophysiology and epidemiologic importance. despite their epidemiologic significance, information on genetic diversity, occurrence and seasonal and spatial distribution patterns of the cx. pipiens complex is still insufficient. assessment of seasonal and spatial distribution patterns of culex pipiens forms and their congener cx. torrentium is crucial for the understanding of their vector-pathogen dynamics.201627067139
high-throughput screening to enhance oncolytic virus immunotherapy.high-throughput screens can rapidly scan and capture large amounts of information across multiple biological parameters. although many screens have been designed to uncover potential new therapeutic targets capable of crippling viruses that cause disease, there have been relatively few directed at improving the efficacy of viruses that are used to treat disease. oncolytic viruses (ovs) are biotherapeutic agents with an inherent specificity for treating malignant disease. certain ov platforms - i ...201627579293
autophagy negatively regulates transmissible gastroenteritis virus replication.autophagy is an evolutionarily ancient pathway that has been shown to be important in the innate immune defense against several viruses. however, little is known about the regulatory role of autophagy in transmissible gastroenteritis virus (tgev) replication. in this study, we found that tgev infection increased the number of autophagosome-like double- and single-membrane vesicles in the cytoplasm of host cells, a phenomenon that is known to be related to autophagy. in addition, virus replicatio ...201627029407
lv305, a dendritic cell-targeting integration-deficient zvex(tm)-based lentiviral vector encoding ny-eso-1, induces potent anti-tumor immune response.we have engineered an integration-deficient lentiviral vector, lv305, to deliver the tumor antigen ny-eso-1 to human dendritic cells in vivo through pseudotyping with a modified sindbis virus envelop protein. mice immunized once with lv305 developed strong, dose-dependent, multifunctional, and cytotoxic ny-eso-1-specific cluster of differentiation 8 (cd8) t cells within 14 days post-immunization and could be boosted with lv305 at least twice to recall peak-level cd8 t-cell responses. immunizatio ...201627626061
middle east respiratory syndrome coronavirus ns4b protein inhibits host rnase l activation.middle east respiratory syndrome coronavirus (mers-cov) is the first highly pathogenic human coronavirus to emerge since severe acute respiratory syndrome coronavirus (sars-cov) in 2002. like many coronaviruses, mers-cov carries genes that encode multiple accessory proteins that are not required for replication of the genome but are likely involved in pathogenesis. evasion of host innate immunity through interferon (ifn) antagonism is a critical component of viral pathogenesis. the ifn-inducible ...201627025250
emergence of a large-plaque variant in mice infected with coxsackievirus b3.coxsackieviruses are enteric viruses that frequently infect humans. to examine coxsackievirus pathogenesis, we orally inoculated mice with the coxsackievirus b3 (cvb3) nancy strain. using hela cell plaque assays with agar overlays, we noticed that some fecal viruses generated plaques >100 times as large as inoculum viruses. these large-plaque variants emerged following viral replication in several different tissues. we identified a single amino acid change, n63y, in the vp3 capsid protein that w ...201627025249
dissecting virus infectious cycles by cryo-electron microscopy. 201627362353
viral inhibition of the ifn-induced jak/stat signalling pathway: development of live attenuated vaccines by mutation of viral-encoded ifn-antagonists.the interferon (ifn) induced anti-viral response is amongst the earliest and most potent of the innate responses to fight viral infection. the induction of the janus kinase/signal transducer and activation of transcription (jak/stat) signalling pathway by ifns leads to the upregulation of hundreds of interferon stimulated genes (isgs) for which, many have the ability to rapidly kill viruses within infected cells. during the long course of evolution, viruses have evolved an extraordinary range of ...201627367734
tnfα impairs rhabdoviral clearance by inhibiting the host autophagic antiviral response.tnfα is a pleiotropic pro-inflammatory cytokine with a key role in the activation of the immune system to fight viral infections. despite its antiviral role, a few viruses might utilize the host produced tnfα to their benefit. some recent reports have shown that anti-tnfα therapies could be utilized to treat certain viral infections. however, the underlying mechanisms by which tnfα can favor virus replication have not been identified. here, a rhabdoviral infection model in zebrafish allowed us t ...201627351838
the strica homolog aacasps16 is involved in apoptosis in the yellow fever vector, aedes albopictus.caspases are a family of cysteine proteases playing essential roles during apoptosis. seven caspases identified in drosophila were dronc, dredd, strica, dcp-1, decay, drice and damm. among them, strica is an insect-specific caspase containing a long serine- and threonine- rich prodomain, of which function is not yet well studied. here we identified a homolog of strica from aedes albopictus, named as aacasps16. aacasps16 encoded a protein containing a putative serine- and threonine-rich prodomain ...201627351972
suppression of kaposi's sarcoma-associated herpesvirus infection and replication by 5'-amp-activated protein kinase.the host intracellular antiviral restriction factors inhibit viral infection and replication. the 5'-amp-activated protein kinase (ampk) is a cellular energy sensor regulating metabolic homeostasis. activated ampk inhibits the replication of numerous rna viruses but enhances the entry of vaccinia virus. however, the role of ampk in herpesvirus infection is unclear. in this study, we showed that the constitutive ampk activity restricted kaposi's sarcoma-associated herpesvirus (kshv) lytic replica ...201627147746
the emerging duck flavivirus is not pathogenic for primates and is highly sensitive to mammalian interferon antiviral signaling.flaviviruses pose a significant threat to both animals and humans. recently, a novel flavivirus, duck tembusu virus (dtmuv), was identified to be the causative agent of a serious duck viral disease in asia. its rapid spread, expanding host range, and uncertain transmission routes have raised substantial concerns regarding its potential threats to nonavian hosts, including humans. here, we demonstrate that dtmuv is not pathogenic for nonhuman primates and is highly sensitive to mammal type i inte ...201627147750
recent advances in lentiviral vaccines for hiv-1 infection.the development of an effective hiv vaccine to prevent and/or cure hiv remains a global health priority. given their central role in the initiation of adaptive immune responses, dendritic cell (dc)-based vaccines are being increasingly explored as immunotherapeutic strategies to enhance hiv-specific t cells in infected individuals and, thus, promote immune responses that may help facilitate a functional cure. hiv-1-based lentiviral (lv) vectors have inherent advantages as dc vaccine vectors due ...201627446074
mosquito saliva increases endothelial permeability in the skin, immune cell migration, and dengue pathogenesis during antibody-dependent enhancement.dengue remains the most prevalent arthropod-borne viral disease in humans. while probing for blood vessels, aedes aegypti and ae. albopictus mosquitoes transmit the four serotypes of dengue virus (denv1-4) by injecting virus-containing saliva into the skin. even though arthropod saliva is known to facilitate transmission and modulate host responses to other pathogens, the full impact of mosquito saliva on dengue pathogenesis is still not well understood. inoculating mice lacking the interferon-α ...201627310141
receptor-targeted nipah virus glycoproteins improve cell-type selective gene delivery and reveal a preference for membrane-proximal cell attachment.receptor-targeted lentiviral vectors (lvs) can be an effective tool for selective transfer of genes into distinct cell types of choice. moreover, they can be used to determine the molecular properties that cell surface proteins must fulfill to act as receptors for viral glycoproteins. here we show that lvs pseudotyped with receptor-targeted nipah virus (niv) glycoproteins effectively enter into cells when they use cell surface proteins as receptors that bring them closely enough to the cell memb ...201627281338
a universal next-generation sequencing protocol to generate noninfectious barcoded cdna libraries from high-containment rna viruses.several biosafety level 3 and/or 4 (bsl-3/4) pathogens are high-consequence, single-stranded rna viruses, and their genomes, when introduced into permissive cells, are infectious. moreover, many of these viruses are select agents (sas), and their genomes are also considered sas. for this reason, cdnas and/or their derivatives must be tested to ensure the absence of infectious virus and/or viral rna before transfer out of the bsl-3/4 and/or sa laboratory. this tremendously limits the capacity to ...201627822536
deah-rha helicase•znf cofactor systems in kinetoplastid rna editing and evolutionarily distant rna processes.multi-zinc finger proteins are an emerging class of cofactors in deah-rha rna helicases across highly divergent eukaryotic lineages. deah-rha helicase•zinc finger cofactor partnerships predate the split of kinetoplastid protozoa, which include several human pathogens, from other eukaryotic lineages 100-400 ma. despite a long evolutionary history, the prototypical deah-rha domains remain highly conserved. this short review focuses on a recently identified deah-rha helicase•zinc finger cofactor sy ...201627540585
a tale of two rnas during viral infection: how viruses antagonize mrnas and small non-coding rnas in the host cell.viral infection initiates an array of changes in host gene expression. many viruses dampen host protein expression and attempt to evade the host anti-viral defense machinery. host gene expression is suppressed at several stages of host messenger rna (mrna) formation including selective degradation of translationally competent messenger rnas. besides mrnas, host cells also express a variety of noncoding rnas, including small rnas, that may also be subject to inhibition upon viral infection. in th ...201627271653
a glance at subgenomic flavivirus rnas and micrornas in flavivirus infections.the family flaviviridae comprises a wide variety of viruses that are distributed worldwide, some of which are associated with high rates of morbidity and mortality. there are neither vaccines nor antivirals for most flavivirus infections, reinforcing the importance of research on different aspects of the viral life cycle. during infection, cytoplasmic accumulation of rna fragments mainly originating from the 3' utrs, which have been designated subgenomic flavivirus rnas (sfrnas), has been detect ...201627233361
entry sites of venezuelan and western equine encephalitis viruses in the mouse central nervous system following peripheral infection.venezuelan and western equine encephalitis viruses (veev and weev; alphavirus; togaviridae) are mosquito-borne pathogens causing central nervous system (cns) disease in humans and equids. adult cd-1 mice also develop cns disease after infection with veev and weev. adult cd-1 mice infected by the intranasal (i.n.) route, showed that veev and weev enter the brain through olfactory sensory neurons (osns). in this study, we injected the mouse footpad with recombinant weev (mcmillan) or veev (subtype ...201627053560
suppression of usp18 potentiates the anti-hbv activity of interferon alpha in hepg2.2.15 cells via jak/stat signaling.ubiquitin-specific protease 18 (usp18, also known as ubp43) has both interferon stimulated gene 15 (isg15) dependent and isg15-independent functions. by silencing the expression of usp18 in hepg2.2.15 cells, we studied the effect of usp18 on the anti-hbv activity of ifn-f and demonstrated that knockdown of usp18 significantly inhibited the hbv expression and increased the expression of isgs. levels of hepatitis b virus surface antigen (hbsag), hepatitis b virus e antigen (hbeag), hbv dna and int ...201627227879
a new defective helper rna to produce recombinant sindbis virus that infects neurons but does not propagate.recombinant sindbis viruses are important tools in neuroscience because they combine rapid and high transgene expression with a capacity to carry large transgenes. currently, two packaging systems based on the defective helper (dh) rnas dh(26s)5'sin and dh-bb(trna;te12) are available for generating recombinant sindbis virus that is neurotropic (able to infect neurons and potentially other cells). both systems produce a fraction of viral particles that can propagate beyond the primary infected ne ...201627252627
hepatitis c virus infection induces autophagy as a prosurvival mechanism to alleviate hepatic er-stress response.hepatitis c virus (hcv) infection frequently leads to chronic liver disease, liver cirrhosis and hepatocellular carcinoma (hcc). the molecular mechanisms by which hcv infection leads to chronic liver disease and hcc are not well understood. the infection cycle of hcv is initiated by the attachment and entry of virus particles into a hepatocyte. replication of the hcv genome inside hepatocytes leads to accumulation of large amounts of viral proteins and rna replication intermediates in the endopl ...201627223299
a de novo transcriptome analysis shows that modulation of the jak-stat signaling pathway by salmonid alphavirus subtype 3 favors virus replication in macrophage/dendritic-like to-cells.the janus kinase (jak) and signaling transducer activator of transcription (stat) pathway mediates the signaling of genes required for cellular development and homeostasis. to elucidate the effect of type i ifn on the jak/stat pathway in salmonid alphavirus subtype 3 (sav3) infected macrophage/dendritic like to-cells derived from atlantic salmon (salmo salar l) headkidney leukocytes, we used a differential transcriptome analysis by rna-seq and the kyoto encyclopedia of genes and genomes (keggs) ...201627215196
isg15 deficiency and increased viral resistance in humans but not mice.isg15 is an interferon (ifn)-α/β-induced ubiquitin-like protein. it exists as a free molecule, intracellularly and extracellularly, and conjugated to target proteins. studies in mice have demonstrated a role for isg15 in antiviral immunity. by contrast, human isg15 was shown to have critical immune functions, but not in antiviral immunity. namely, free extracellular isg15 is crucial in ifn-γ-dependent antimycobacterial immunity, while free intracellular isg15 is crucial for usp18-mediated downre ...201627193971
mutagenesis of coronavirus nsp14 reveals its potential role in modulation of the innate immune response.coronavirus (cov) nonstructural protein 14 (nsp14) is a 60-kda protein encoded by the replicase gene that is part of the replication-transcription complex. it is a bifunctional enzyme bearing 3'-to-5' exoribonuclease (exon) and guanine-n7-methyltransferase (n7-mtase) activities. exon hydrolyzes single-stranded rnas and double-stranded rnas (dsrnas) and is part of a proofreading system responsible for the high fidelity of cov replication. nsp14 n7-mtase activity is required for viral mrna cap syn ...201627009949
analysis of the contribution of hemocytes and autophagy to drosophila antiviral immunity.antiviral immunity in the model organism drosophila melanogaster involves the broadly active intrinsic mechanism of rna interference (rnai) and virus-specific inducible responses. here, using a panel of six viruses, we investigated the role of hemocytes and autophagy in the control of viral infections. injection of latex beads to saturate phagocytosis, or genetic depletion of hemocytes, resulted in decreased survival and increased viral titers following infection with cricket paralysis virus (cr ...201627009948
genome investigations of vector competence in aedes aegypti to inform novel arbovirus disease control approaches.dengue (denv), yellow fever, chikungunya, and zika virus transmission to humans by a mosquito host is confounded by both intrinsic and extrinsic variables. besides virulence factors of the individual arboviruses, likelihood of virus transmission is subject to variability in the genome of the primary mosquito vector, aedes aegypti. the "vectorial capacity" of a. aegypti varies depending upon its density, biting rate, and survival rate, as well as its intrinsic ability to acquire, host and transmi ...201627809220
acyclic nucleoside phosphonates containing the amide bond.to study the influence of a linker rigidity and donor-acceptor properties, the p-ch2-o-chr- fragment in acyclic nucleoside phosphonates (e.g., acyclovir, tenofovir) was replaced by the p-ch2-hn-c(o)- residue. the respective phosphonates were synthesized in good yields by coupling the straight chain of ω-aminophosphonates and nucleobase-derived acetic acids with edc. based on the (1)h and (13)c nmr data, the unrestricted rotation within the methylene and 1,2-ethylidene linkers in phosphonates fro ...201627881885
crystal structure of glycoprotein c from a hantavirus in the post-fusion conformation.hantaviruses are important emerging human pathogens and are the causative agents of serious diseases in humans with high mortality rates. like other members in the bunyaviridae family their m segment encodes two glycoproteins, gn and gc, which are responsible for the early events of infection. hantaviruses deliver their tripartite genome into the cytoplasm by fusion of the viral and endosomal membranes in response to the reduced ph of the endosome. unlike phleboviruses (e.g. rift valley fever vi ...201627783673
mutagenic effects of ribavirin on hepatitis e virus-viral extinction versus selection of fitness-enhancing mutations.hepatitis e virus (hev), an important agent of viral hepatitis worldwide, can cause severe courses of infection in pregnant women and immunosuppressed patients. to date, hev infections can only be treated with ribavirin (rbv). major drawbacks of this therapy are that rbv is not approved for administration to pregnant women and that the virus can acquire mutations, which render the intra-host population less sensitive or even resistant to rbv. one of the proposed modes of action of rbv is a direc ...201627754363
interferon gamma: influence on neural stem cell function in neurodegenerative and neuroinflammatory disease.interferon-gamma (ifnγ), a pleiotropic cytokine, is expressed in diverse neurodegenerative and neuroinflammatory conditions. its protective mechanisms are well documented during viral infections in the brain, where ifnγ mediates non-cytolytic viral control in infected neurons. however, ifnγ also plays both protective and pathological roles in other central nervous system (cns) diseases. of the many neural cells that respond to ifnγ, neural stem/progenitor cells (nspcs), the only pluripotent cell ...201627774000
amyloid-β effects on synapses and memory require ampa receptor subunit glua3.amyloid-β (aβ) is a prime suspect for causing cognitive deficits during the early phases of alzheimer's disease (ad). experiments in ad mouse models have shown that soluble oligomeric clusters of aβ degrade synapses and impair memory formation. we show that all aβ-driven effects measured in these mice depend on ampa receptor (ampar) subunit glua3. hippocampal neurons that lack glua3 were resistant against aβ-mediated synaptic depression and spine loss. in addition, aβ oligomers blocked long-term ...201627708157
high insecticides resistance in culex pipiens (diptera: culicidae) from tehran, capital of iran.during recent years transmission of dirofilaria immitis (dog heart worm) by culex pipiens and west nile virus have been reported from iran. the present study was preformed for evaluating the susceptibility status of cx. pipiens collected from capital city of tehran, iran.201628032100
climate change influences on the global potential distribution of the mosquito culex quinquefasciatus, vector of west nile virus and lymphatic filariasis.rapid emergence of most vector-borne diseases (vbds) may be associated with range expansion of vector populations. culex quinquefasciatus say 1823 is a potential vector of west nile virus, saint louis encephalitis virus, and lymphatic filariasis. we estimated the potential distribution of cx. quinquefasciatus under both current and future climate conditions. the present potential distribution of cx. quinquefasciatus showed high suitability across low-latitude parts of the world, reflecting the c ...201627695107
a 3'-end structure in rna2 of a crinivirus is essential for viral rna synthesis and contributes to replication-associated translation activity.the terminal ends in the genome of rna viruses contain features that regulate viral replication and/or translation. we have identified a y-shaped structure (yss) in the 3' terminal regions of the bipartite genome of lettuce chlorosis virus (lcv), a member in the genus crinivirus (family closteroviridae). the yss is the first in this family of viruses to be determined using selective 2'-hydroxyl acylation analyzed by primer extension (shape). using luciferase constructs/replicons, in vivo and in ...201627694962
differential expression pattern of vago in bumblebee (bombus terrestris), induced by virulent and avirulent virus infections.viruses are one of the main drivers of the decline of domesticated and wild bees but the mechanisms of antiviral immunity in pollinators are poorly understood. recent work has suggested that next to the small interfering rna (sirna) pathway other immune-related pathways play a role in the defense of the bee hosts against viral infection. in addition, vago plays a role in the cross-talk between the innate immune pathways in culex mosquito cells. here we describe the vago orthologue in bumblebees ...201627680717
quantification of virus particles using nanopore-based resistive-pulse sensing techniques.viruses have drawn much attention in recent years due to increased recognition of their important roles in virology, immunology, clinical diagnosis, and therapy. because the biological and physical properties of viruses significantly impact their applications, quantitative detection of individual virus particles has become a critical issue. however, due to various inherent limitations of conventional enumeration techniques such as infectious titer assays, immunological assays, and electron micro ...201627713738
morphological abnormalities and cell death in the asian citrus psyllid (diaphorina citri) midgut associated with candidatus liberibacter asiaticus.candidatus liberibacter asiaticus (clas) is a phloem-limited, gram-negative, fastidious bacterium that is associated with the development of citrus greening disease, also known as huanglongbing (hlb). clas is transmitted by the asian citrus psyllid (acp) diaphorina citri, in a circulative manner. two major barriers to transmission within the insect are the midgut and the salivary glands. we performed a thorough microscopic analysis within the insect midgut following exposure to clas-infected cit ...201627630042
amphotericin b inhibits enterovirus 71 replication by impeding viral entry.enterovirus 71 (ev71) infection causes hand-foot-and-mouth disease that leads to cardiopulmonary complications and death in young children. there is thus an urgent need to find new treatments to control ev71 infection. in this study, we report potent inhibition of ev71 by a polyene antibiotic amphotericin b. amphotericin b profoundly diminished the expression of ev71 rna and viral proteins in the rd cells and the hek293 cells. as a result, ev71 production was inhibited by amphotericin b with an ...201627608771
m2bp inhibits hiv-1 virion production in a vimentin filaments-dependent manner.m2bp (also called 90k) is an interferon-stimulated gene product that is upregulated in hiv-1 infection. a recent study revealed that m2bp reduces the infectivity of hiv-1 by inhibiting the processing of the viral envelope protein. here we report that in addition to reducing viral infectivity, m2bp inhibits hiv-1 virion production. we provide evidence showing that m2bp inhibits hiv-1 gag trafficking to the plasma membrane in a vimentin-dependent manner. when vimentin filaments were collapsed by t ...201627604950
global profiling of the cellular alternative rna splicing landscape during virus-host interactions.alternative splicing (as) is a central mechanism of genetic regulation which modifies the sequence of rna transcripts in higher eukaryotes. as has been shown to increase both the variability and diversity of the cellular proteome by changing the composition of resulting proteins through differential choice of exons to be included in mature mrnas. in the present study, alterations to the global rna splicing landscape of cellular genes upon viral infection were investigated using mammalian reoviru ...201627598998
excess cerebral tnf causing glutamate excitotoxicity rationalizes treatment of neurodegenerative diseases and neurogenic pain by anti-tnf agents.the basic mechanism of the major neurodegenerative diseases, including neurogenic pain, needs to be agreed upon before rational treatments can be determined, but this knowledge is still in a state of flux. most have agreed for decades that these disease states, both infectious and non-infectious, share arguments incriminating excitotoxicity induced by excessive extracellular cerebral glutamate. excess cerebral levels of tumor necrosis factor (tnf) are also documented in the same group of disease ...201627596607
trim14 inhibits hepatitis c virus infection by spry domain-dependent targeted degradation of the viral ns5a protein.tripartite motif 14 (trim14) was reported to function as a mitochondrial signaling adaptor in mediating innate immune responses. however, the involvement of trim14 in host defense against viral infection and molecular mechanisms remain unclear. here, we demonstrated that enforced expression of trim14 could potently inhibit the infection and replication of hcv in hepatocytes, whereas trim14 knockout cells became more susceptible to hcv infection. interestingly, further experiments revealed that s ...201627578425
consecutive inhibition of isg15 expression and isgylation by cytomegalovirus regulators.interferon-stimulated gene 15 (isg15) encodes an ubiquitin-like protein that covalently conjugates protein. protein modification by isg15 (isgylation) is known to inhibit the replication of many viruses. however, studies on the viral targets and viral strategies to regulate isgylation-mediated antiviral responses are limited. in this study, we show that human cytomegalovirus (hcmv) replication is inhibited by isgylation, but the virus has evolved multiple countermeasures. hcmv-induced isg15 expr ...201627564865
type-1 angiotensin receptor signaling in central nervous system myeloid cells is pathogenic during fatal alphavirus encephalitis in mice.alphaviruses can cause fatal encephalitis in humans. natural infections occur via the bite of infected mosquitos, but aerosol transmissibility makes some of these viruses potential bioterrorism agents. central nervous system (cns) host responses contribute to alphavirus pathogenesis in experimental models and are logical therapeutic targets. we investigated whether reactive oxygen species (ros) generated by nicotinamide adenine dinucleotide phosphate (nadph) oxidase (nox) activity within the cns ...201627562117
working with zika and usutu viruses in vitro.usutu (usuv) and zika (zikv) viruses are emerging arboviruses of significant medical and veterinary importance. these viruses have not been studied as well as other medically important arboviruses such as west nile (wnv), dengue (denv), or chikungunya (chikv) viruses. as such, information regarding the behavior of zikv and usuv viruses in the laboratory is dated. usutu virus re-emerged in austria in 2001 and has since spread throughout the european and asian continents causing significant mortal ...201627541001
functional translational readthrough: a systems biology perspective.translational readthrough (tr) has come into renewed focus because systems biology approaches have identified the first human genes undergoing functional translational readthrough (ftr). ftr creates functional extensions to proteins by continuing translation of the mrna downstream of the stop codon. here we review recent developments in tr research with a focus on the identification of ftr in humans and the systems biology methods that have spurred these discoveries.201627490485
cytoplasmic drosha activity generated by alternative splicing.rnase iii enzyme drosha interacts with dgcr8 to form the microprocessor, initiating canonical microrna (mirna) maturation in the nucleus. here, we re-evaluated where drosha functions in cells using drosha and/or dgcr8 knock out (ko) cells and cleavage reporters. interestingly, a truncated drosha mutant located exclusively in the cytoplasm cleaved pri-mirna effectively in a dgcr8-dependent manner. in addition, we demonstrated that in vitro generated pri-mirnas when transfected into cells could be ...201627471035
the role of phlebovirus glycoproteins in viral entry, assembly and release.bunyaviruses are enveloped viruses with a tripartite rna genome that can pose a serious threat to animal and human health. members of the phlebovirus genus of the family bunyaviridae are transmitted by mosquitos and ticks to humans and include highly pathogenic agents like rift valley fever virus (rvfv) and severe fever with thrombocytopenia syndrome virus (sftsv) as well as viruses that do not cause disease in humans, like uukuniemi virus (uukv). phleboviruses and other bunyaviruses use their e ...201627455305
exaptive origins of regulated mrna decay in eukaryotes.eukaryotic gene expression is extensively controlled at the level of mrna stability and the mechanisms underlying this regulation are markedly different from their archaeal and bacterial counterparts. we propose that two such mechanisms, nonsense-mediated decay (nmd) and motif-specific transcript destabilization by ccch-type zinc finger rna-binding proteins, originated as a part of cellular defense against rna pathogens. these branches of the mrna turnover pathway might have been used by primeva ...201627438915
n-terminal domain of feline calicivirus (fcv) proteinase-polymerase contributes to the inhibition of host cell transcription.feline calicivirus (fcv) infection results in the inhibition of host protein synthesis, known as "shut-off". however, the precise mechanism of shut-off remains unknown. here, we found that the fcv strain 2280 proteinase-polymerase (pp) protein can suppress luciferase reporter gene expression driven by endogenous and exogenous promoters. furthermore, we found that the n-terminal 263 aa of pp (ppn-263) determined its shut-off activity using the expression of truncated proteins. however, the same d ...201627447663
a viral mrna motif at the 3'-untranslated region that confers translatability in a cell-specific manner. implications for virus evolution.sindbis virus (sinv) mrnas contain several motifs that participate in the regulation of their translation. we have discovered a motif at the 3' untranslated region (utr) of viral mrnas, constituted by three repeated sequences, which is involved in the translation of both sinv genomic and subgenomic mrnas in insect, but not in mammalian cells. these data illustrate for the first time that an element present at the 3'-utr confers translatability to mrnas from an animal virus in a cell-specific man ...201626755446
hippocampal dendritic spines are segregated depending on their actin polymerization.dendritic spines are mushroom-shaped protrusions of the postsynaptic membrane. spines receive the majority of glutamatergic synaptic inputs. their morphology, dynamics, and density have been related to synaptic plasticity and learning. the main determinant of spine shape is filamentous actin. using frap, we have reexamined the actin dynamics of individual spines from pyramidal hippocampal neurons, both in cultures and in hippocampal organotypic slices. our results indicate that, in cultures, the ...201626881098
cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances.oncolytic viruses are multifunctional anticancer agents with huge clinical potential, and have recently passed the randomized phase iii clinical trial hurdle. both wild-type and engineered viruses have been selected for targeting of specific cancers, to elicit cytotoxicity, and also to generate antitumor immunity. single-agent oncolytic virotherapy treatments have resulted in modest effects in the clinic. there is increasing interest in their combination with cytotoxic agents, radiotherapy and i ...201627579292
activation of the dna damage response by rna viruses.rna viruses are a genetically diverse group of pathogens that are responsible for some of the most prevalent and lethal human diseases. numerous viruses introduce dna damage and genetic instability in host cells during their lifecycles and some species also manipulate components of the dna damage response (ddr), a complex and sophisticated series of cellular pathways that have evolved to detect and repair dna lesions. activation and manipulation of the ddr by dna viruses has been extensively stu ...201626751489
lncrna oip5-as1/cyrano sponges rna-binding protein hur.the function of the vast majority of mammalian long noncoding (lnc) rnas remains unknown. here, analysis of a highly abundant mammalian lncrna, oip5-as1, known as cyrano in zebrafish, revealed that oip5-as1 reduces cell proliferation. in human cervical carcinoma hela cells, the rna-binding protein hur, which enhances cell proliferation, associated with oip5-as1 and stabilized it. tagging oip5-as1 with ms2 hairpins to identify associated micrornas revealed that mir-424 interacted with oip5-as1 an ...201626819413
seropositivity for west nile virus antibodies in patients affected by myasthenia gravis.myasthenia gravis (mg) is an autoimmune neuromuscular disease characterized by varying degrees of weakness of the skeletal muscles. specific auto-antibodies against acetylcholine receptor (achr) are present in the majority of mg patients, although the main cause behind its development still remains unclear. recently mg development following west nile virus (wnv) infection has been described in patients without any earlier evidence of mg. it is known that infectious agents trigger immune response ...201626858791
apoptosis, autophagy and unfolded protein response pathways in arbovirus replication and pathogenesis.arboviruses are pathogens that widely affect the health of people in different communities around the world. recently, a few successful approaches toward production of effective vaccines against some of these pathogens have been developed, but treatment and prevention of the resulting diseases remain a major health and research concern. the arbovirus infection and replication processes are complex, and many factors are involved in their regulation. apoptosis, autophagy and the unfolded protein r ...201626781343
characterization of ryden (c19orf66) as an interferon-stimulated cellular inhibitor against dengue virus replication.dengue virus (denv) is one of the most important arthropod-borne pathogens that cause life-threatening diseases in humans. however, no vaccine or specific antiviral is available for dengue. as seen in other rna viruses, the innate immune system plays a key role in controlling denv infection and disease outcome. although the interferon (ifn) response, which is central to host protective immunity, has been reported to limit denv replication, the molecular details of how denv infection is modulated ...201626735137
palmitoylation of sindbis virus tf protein regulates its plasma membrane localization and subsequent incorporation into virions.palmitoylation is a reversible, posttranslational modification that helps target proteins to cellular membranes. the alphavirus small membrane proteins 6k and tf have been reported to be palmitoylated and to positively regulate budding. 6k and tf are isoforms that are identical in their n termini but unique in their c termini due to a -1 ribosomal frameshift during translation. in this study, we used cysteine (cys) mutants to test differential palmitoylation of the sindbis virus 6k and tf protei ...201727852864
individual mediodorsal thalamic neurons project to multiple areas of the rat prefrontal cortex: a single neuron-tracing study using virus vectors.the prefrontal cortex has an important role in a variety of cognitive and executive processes, and is generally defined by its reciprocal connections with the mediodorsal thalamic nucleus (md). the rat md is mainly subdivided into three segments, the medial (mdm), central (mdc), and lateral (mdl) divisions, on the basis of the cytoarchitecture and chemoarchitecture. the md segments are known to topographically project to multiple prefrontal areas at the population level: the mdm mainly to the pr ...201727275581
neurotropic alphaviruses can propagate without capsid. 201728129638
an icosahedral virus as a fluorescent calibration standard: a method for counting protein molecules in cells by fluorescence microscopy.the ability to replace genes coding for cellular proteins with dna that codes for fluorescent protein-tagged versions opens the way to counting the number of molecules of each protein component of macromolecular assemblies in vivo by measuring fluorescence microscopically. converting fluorescence to absolute numbers of molecules requires a fluorescent standard whose molecular composition is known precisely. in this report, the construction, properties and mode of using a set of fluorescence cali ...201728328099
translation of sindbis subgenomic mrna is independent of eif2, eif2a and eif2d.translation of sindbis virus subgenomic mrna (sgmrna) can occur after inactivation of eif2 by phosphorylation in mammalian cells. several studies have suggested that eif2 can be replaced by eif2a or eif2d. hap1 human cell lines knocked-out for eif2a, eif2d or both by crispr/cas9 genome engineering were compared with wild-type (wt) cells to test the potential role of eif2a and eif2d in translation. sindbis virus infection was comparable between the four cell lines. moreover, synthesis of viral pr ...201728240315
microbiota activates imd pathway and limits sindbis infection in aedes aegypti.aedes aegypti is the main vector of important arboviruses such as dengue, zika and chikungunya. during infections mosquitoes can activate the immune pathways toll, imd and jak/stat to limit pathogen replication.201728231846
mitochondrial damage elicits a tcdd-inducible poly(adp-ribose) polymerase-mediated antiviral response.the innate immune system senses rna viruses by pattern recognition receptors (prrs) and protects the host from virus infection. prrs mediate the production of immune modulatory factors and direct the elimination of rna viruses. here, we show a unique prr that mediates antiviral response. tetrachlorodibenzo-p-dioxin (tcdd)-inducible poly(adp ribose) polymerase (tiparp), a cysteine3 histidine (ccch)-type zinc finger-containing protein, binds to sindbis virus (sinv) rna via its zinc finger domain a ...201728213497
spatial and temporal analysis of alphavirus replication and assembly in mammalian and mosquito cells.sindbis virus (sinv [genus alphavirus, family togaviridae]) is an enveloped, mosquito-borne virus. alphaviruses cause cytolytic infections in mammalian cells while establishing noncytopathic, persistent infections in mosquito cells. mosquito vector adaptation of alphaviruses is a major factor in the transmission of epidemic strains of alphaviruses. though extensive studies have been performed on infected mammalian cells, the morphological and structural elements of alphavirus replication and ass ...201728196962
dynamics of molecular evolution in rna virus populations depend on sudden versus gradual environmental change.understanding the dynamics of molecular adaptation is a fundamental goal of evolutionary biology. while adaptation to constant environments has been well characterized, the effects of environmental complexity remain seldom studied. one simple but understudied factor is the rate of environmental change. here we used experimental evolution with rna viruses to investigate whether evolutionary dynamics varied based on the rate of environmental turnover. we used whole-genome next-generation sequencin ...201728121018
trim25 enhances the antiviral action of zinc-finger antiviral protein (zap).the host factor and interferon (ifn)-stimulated gene (isg) product, zinc-finger antiviral protein (zap), inhibits a number of diverse viruses by usurping and intersecting with multiple cellular pathways. to elucidate its antiviral mechanism, we perform a loss-of-function genome-wide rnai screen to identify cellular cofactors required for zap antiviral activity against the prototype alphavirus, sindbis virus (sinv). in order to exclude off-target effects, we carry out stringent confirmatory assay ...201728060952
inactivation of viruses by pasteurization at 60 °c for 10 h with and without 40% glucose as stabilizer during a new manufacturing process of α2-macroglobulin from cohn fraction iv.pasteurization is regularly used to inactivate viruses for the safety of plasma derivatives. influence of pasteurization at 60 °c for 10 h on α2-macroglobulin activity and virus inactivation were studied. with 40% sugar as stabilizers more than 70% α2-macroglobulin activity was reserved after pasteurization compared with 20% in control. glucose presented a better activity protection effect than sucrose and maltose. by pasteurization without stabilizer the virus titers of pseudorabies virus, sind ...201728215695
alphavirus-based vaccines.alphavirus-based vectors have been engineered from semliki forest virus, sindbis virus, and venezuelan equine encephalitis virus and applied for vaccine development. immunization in preclinical animal models has been conducted with naked rna replicons, recombinant viral particles and layered dna-rna vectors. most commonly, the targets for the immunization have been viral surface proteins and tumor antigens, which have elicited strong immune responses and even provided protection against challeng ...201728374252
discovery of a novel antiviral agent targeting the nonstructural protein 4 (nsp4) of chikungunya virus.chikungunya fever (chikf) is caused by chikungunya virus (chikv) infection which is a re-emerging mosquito-borne zoonosis. at present, there are no approved therapeutics for chikf. herein, we have investigated candidate compounds which can inhibit chikv infection. screening of chemical compound libraries were performed and one candidate, a benzimidazole-related compound designated compound-a was found to inhibit infection by several chikv strains and a sindbis virus strain at nanomolar concentra ...201728236746
selective transduction of astrocytic and neuronal cns subpopulations by lentiviral vectors pseudotyped with chikungunya virus envelope.lentiviral vectors are gene delivery vehicles that integrate into the host genome of dividing and non-dividing mammalian cells facilitating long-term transgene expression. lentiviral vector versatility is greatly increased by incorporating heterologous viral envelope proteins onto the vector particles instead of the native envelope, conferring on these pseudotyped vectors a modified tropism and host range specificity. we investigated the pseudotyping efficiency of hiv-1 based lentiviral vectors ...201728152379
obatoclax inhibits alphavirus membrane fusion by neutralizing the acidic environment of endocytic compartments.as new pathogenic viruses continue to emerge, it is paramount to have intervention strategies that target a common denominator in these pathogens. the fusion of viral and cellular membranes during viral entry is one such process that is used by many pathogenic viruses, including chikungunya virus, west nile virus, and influenza virus. obatoclax, a small-molecule antagonist of the bcl-2 family of proteins, was previously determined to have activity against influenza a virus and also sindbis virus ...201727993855
ablation of programmed -1 ribosomal frameshifting in venezuelan equine encephalitis virus results in attenuated neuropathogenicity.the alphaviruses venezuelan equine encephalitis virus (veev), eastern equine encephalitis virus (eeev), and western equine encephalitis virus (weev) are arthropod-borne positive-strand rna viruses that are capable of causing acute and fatal encephalitis in many mammals, including humans. veev was weaponized during the cold war and is recognized as a select agent. currently, there are no fda-approved vaccines or therapeutics for these viruses. the spread of veev and other members of this family d ...201727852852
trim25 is required for the antiviral activity of zinc-finger antiviral protein (zap).zinc-finger antiviral protein (zap) is a host factor that specifically inhibits the replication of certain viruses by binding to viral mrnas, and repressing the translation and/or promoting the degradation of target mrna. in addition, zap regulates the expression of certain cellular genes. here, we report that tripartite motif-containing protein 25 (trim25), a ubiquitin e3 ligase, is required for the antiviral activity of zap. downregulation of endogenous trim25 abolished zap's antiviral activit ...201728202764
imaging of viral neuroinvasion in the zebrafish reveals that sindbis and chikungunya viruses favour different entry routes.alphaviruses, such as chikungunya virus (chikv) and sindbis virus (sinv), are vector-borne pathogens that cause acute illnesses in humans and are sometimes associated with neuropathies, especially in infants and elderly patients. little is known about their mechanism of entry into the central nervous system (cns), even for sinv, which has been used extensively as a model for viral encephalopathies. we previously established a chikv infection model in the optically transparent zebrafish larva; he ...201728483796
identification of a newly isolated getah virus in the china-laos border, china.in this study, we isolated a virus strain (yn12031) from specimens of armigeres subalbatus collected in the china-laos border. bhk-21 cells infected with yn12031 exhibited an evident cytopathic effect (cpe) 32 h post-infection. the virus particles were spherical, 70 nm in diameter, and enveloped; they also featured surface fibers. molecular genetic analysis revealed that yn12031 was closely related to alpha viruses such as chikungunya virus and sindbis virus, and located in the same clade as mm2 ...201728427491
biological safety of a highly purified 10% liquid intravenous immunoglobulin preparation from human plasma.a highly purified 10% liquid intravenous immunoglobulin, iqymune(®), has been developed using an innovative manufacturing process including an affinity chromatography step for the removal of anti-a and anti-b hemagglutinins.201728508264
partially uncleaved alphavirus replicase forms spherule structures in the presence and absence of rna template.alphaviruses are positive-strand rna viruses expressing their replicase as a polyprotein, p1234, which is cleaved to four final products, nonstructural proteins nsp1 to nsp4. the replicase proteins together with viral rna and host factors form membrane invaginations termed spherules, which act as the replication complexes producing progeny rnas. we have previously shown that the wild-type alphavirus replicase requires a functional rna template and active polymerase to generate spherule structure ...201728701392
application of alphaviral vectors for immunomodulation in cancer therapy.the lack of specific and efficient cancer therapies has influenced the development of novel approaches, such as immunotherapy, which from its original application of immunogenic protein delivery has developed into the use of more sophisticated recombinant gene delivery methods to achieve better safety and efficacy profiles. this approach involves viral and non-viral delivery systems.201728641531
oncolytic alphaviruses in cancer immunotherapy.oncolytic viruses show specific targeting and killing of tumor cells and therefore provide attractive assets for cancer immunotherapy. in parallel to oncolytic viral vectors based on adenoviruses and herpes simplex viruses, oncolytic rna viruses and particularly alphaviruses have been evaluated as delivery vehicles. immunization studies in experimental rodent models for various cancers including glioblastoma, hematologic, hepatocellular, colon, cervix, and lung cancer as well as melanoma have be ...201728417936
h-ras exerts opposing effects on type i interferon responses depending on its activation status.using shrna high-throughput screening, we identified h-ras as a regulator of antiviral activity, whose depletion could enhance sindbis virus replication. further analyses indicated that depletion of h-ras results in a robust increase in vesicular stomatitis virus infection and a decrease in sendai virus (sev)-induced retinoic acid-inducible gene-i-like receptor (rlr) signaling. interestingly, however, ectopic expression of wild-type h-ras results in a biphasic mode of rlr signaling regulation: w ...201728848563
dorsal and ventral parts of thalamic nucleus submedius project to different areas of rat orbitofrontal cortex: a single neuron-tracing study using virus vectors.the rodent orbitofrontal cortex is involved in a variety of cognitive and behavioral functions that require thalamic input to be successfully expressed. although the thalamic nucleus submedius (sm) is a major source of afferents to the orbitofrontal cortex, thalamocortical projection from the sm has not been fully elucidated. in the present study, we first divided the rat sm into dorsal and ventral parts according to the distribution of vesicular glutamate transporter 2-immunoreactive varicositi ...201728833113
identification of interactions between sindbis virus capsid protein and cytoplasmic vrna as novel virulence determinants.alphaviruses are arthropod-borne viruses that represent a significant threat to public health at a global level. while the formation of alphaviral nucleocapsid cores, consisting of cargo nucleic acid and the viral capsid protein, is an essential molecular process of infection, the precise interactions between the two partners are ill-defined. a clip-seq approach was used to screen for candidate sites of interaction between the viral capsid protein and genomic rna of sindbis virus (sinv), a model ...201728662211
wolbachia elevates host methyltransferase expression to block an rna virus early during infection.wolbachia pipientis is an intracellular endosymbiont known to confer host resistance against rna viruses in insects. however, the causal mechanism underlying this antiviral defense remains poorly understood. to this end, we have established a robust arthropod model system to study the tripartite interaction involving sindbis virus and wolbachia strain wmel within its native host, drosophila melanogaster. by leveraging the power of drosophila genetics and a parallel, highly tractable d. melanogas ...201728617844
development and characterization of sindbis virus with encoded fluorescent rna aptamer spinach2 for imaging of replication and immune-mediated changes in intracellular viral rna.viral rna studies often rely on in situ hybridization and reverse transcriptase-pcr to provide snapshots of rna dynamics in infected cells. to facilitate analysis of cellular rnas, aptamers spinach and spinach2 that bind and activate the conditional fluorophore 3, 5-difluoro-4-hydroxybenzylidene imidazolinon have been developed. to determine the feasibility of applying this technology to viral rna, we have used cdna clones of the te strain of sindbis virus (sinv) to construct multiple viruses co ...201728555544
glutamine antagonist-mediated immune suppression decreases pathology but delays virus clearance in mice during nonfatal alphavirus encephalomyelitis.infection of weanling c57bl/6 mice with the te strain of sindbis virus (sinv) causes nonfatal encephalomyelitis associated with hippocampal-based memory impairment that is partially prevented by treatment with 6-diazo-5-oxo-l-norleucine (don), a glutamine antagonist (potter et al., j neurovirol 21:159, 2015). to determine the mechanism(s) of protection, lymph node and central nervous system (cns) tissues from sinv-infected mice treated daily for 1 week with low (0.3mg/kg) or high (0.6mg/kg) dose ...201728531865
operational mosquito and vector-borne diseases surveillance at incirlik air base, turkey.arboviruses on incirlik air base, turkey, pose a threat to military personnel and civilians, but might also be relevant for understanding the threats in neighboring conflict zones such as syria. we reviewed 6 years of mosquito and arbovirus surveillance at incirlik air base. over 6,000 mosquitoes were identified as aedes caspius, anopheles claviger, culex mimeticus, cx. perexiguus, cx. pipiens, cx. sinaiticus, and culiseta longiareolata. almost all of the mosquitoes (more than 90%) were cx. pere ...201728511277
host-feeding patterns of culex mosquitoes in iran.different mosquito-borne pathogens are circulating in iran including sindbis virus, west nile virus, filarioid worms and malaria parasites. however, the local transmission cycles of these pathogenic agents are poorly understood, especially because ecological data on vector species are scarce and there is limited knowledge about the host range; this understanding could help to direct species-specific vector control measurements or to prioritize research.201830587194
arboviruses isolated from the barkedji mosquito-based surveillance system, 2012-2013.a mosquito-based arbovirus surveillance system was set up at barkedji, senegal after the first outbreak of rift valley fever in west africa in 1988. this system was recently updated using more sampling methods and collecting in greater number of ponds and villages sites.201830541472
linkages between chiropteran diversity and ecosystem services for sustainable fragmented forest conservation.this data article informs about chiropteran diversity, new records, ecosystem services and possible pathogen carriers in fragmented forests (sub-divided by utility corridors, man-made structures, untouched and secondary plantations) within districts setiu (setiu research station), hulu terengganu (saok and lasir waterfalls) and besut (gunung tebu forest reserve) of state terengganu, peninsular malaysia. these bats were captured using harp traps and mist nets that were set 10 m apart across flywa ...201830533456
common vole (microtus arvalis) and bank vole (myodes glareolus) derived permanent cell lines differ in their susceptibility and replication kinetics of animal and zoonotic viruses.pathogenesis and reservoir host adaptation of animal and zoonotic viruses are poorly understood due to missing adequate cell culture and animal models. the bank vole (myodes glareolus) and common vole (microtus arvalis) serve as hosts for a variety of zoonotic pathogens. for a better understanding of virus association to a putative animal host, we generated two novel cell lines from bank voles of different evolutionary lineages and two common vole cell lines and assayed their susceptibility, rep ...201931513859
sindbis virus- a wild bird associated zoonotic arbovirus circulates in germany.sindbis virus (sinv) is an arbovirus causing clinical symptoms such as arthritis, rash and fever following human infections in fennoscandia. its transmission cycle involves mosquito species as vectors as well as wild birds that act as natural reservoir hosts. in germany, sinv was first time observed in 2009 in different mosquito species in the upper rhine valley and one year later in a hooded crow in berlin. recently, sinv was also detected repeatedly at various locations in germany in the conte ...201931767092
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