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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
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
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
diagnosis of barmah forest virus infection by a nested real-time sybr green rt-pcr assay.barmah forest virus (bfv) is a mosquito borne (+) ssrna alphavirus found only in australia. it causes rash, myalgia and arthralgia in humans and is usually diagnosed serologically. we developed a real-time pcr assay to detect bfv in an effort to improve diagnosis early in the course of infection. the limit of detection was 16 genome equivalents with a specificity of 100%. fifty five serum samples from bfv-infected patients were tested by the pcr. 52 of 53 antibody-positive samples were pcr negat ...201323935816
zoonotic encephalitides caused by arboviruses: transmission and epidemiology of alphaviruses and flaviviruses.in this review, we mainly focus on zoonotic encephalitides caused by arthropod-borne viruses (arboviruses) of the families flaviviridae (genus flavivirus) and togaviridae (genus alphavirus) that are important in both humans and domestic animals. specifically, we will focus on alphaviruses (eastern equine encephalitis virus, western equine encephalitis virus, venezuelan equine encephalitis virus) and flaviviruses (japanese encephalitis virus and west nile virus). most of these viruses were origin ...201324427764
surveillance for arboviral zoonoses in new zealand birds.given the significant burden that emerging infectious diseases place on global economies and public health, the monitoring and mitigation of, and early response to, potential infectious diseases are of the highest priority. the objective of this study was to survey for known and other potential arboviral zoonoses in multiple bird species at four locations in new zealand.201324478919
a genome-wide analysis of rna pseudoknots that stimulate efficient -1 ribosomal frameshifting or readthrough in animal viruses.programmed -1 ribosomal frameshifting (prf) and stop codon readthrough are two translational recoding mechanisms utilized by some rna viruses to express their structural and enzymatic proteins at a defined ratio. efficient recoding usually requires an rna pseudoknot located several nucleotides downstream from the recoding site. to assess the strategic importance of the recoding pseudoknots, we have carried out a large scale genome-wide analysis in which we used an in-house developed program to d ...201324298557
enhanced arbovirus surveillance with deep sequencing: identification of novel rhabdoviruses and bunyaviruses in australian mosquitoes.viral metagenomics characterizes known and identifies unknown viruses based on sequence similarities to any previously sequenced viral genomes. a metagenomics approach was used to identify virus sequences in australian mosquitoes causing cytopathic effects in inoculated mammalian cell cultures. sequence comparisons revealed strains of liao ning virus (reovirus, seadornavirus), previously detected only in china, livestock-infecting stretch lagoon virus (reovirus, orbivirus), two novel dimarhabdov ...201324314645
the role of e3 in ph protection during alphavirus assembly and exit.alphaviruses are small enveloped viruses whose surface is covered by spikes composed of trimers of e2/e1 glycoprotein heterodimers. during virus entry, the e2/e1 dimer dissociates within the acidic endosomal environment, freeing the e1 protein to mediate fusion of the viral and endosome membranes. e2 is synthesized as a precursor, p62, which is cleaved by furin in the late secretory pathway to produce mature e2 and a small peripheral glycoprotein, e3. the immature p62/e1 dimer is acid resistant, ...201323864626
therapeutic targeting of autophagy in disease: biology and pharmacology.autophagy, a process of self-digestion of the cytoplasm and organelles through which cellular components are recycled for reuse or energy production, is an evolutionarily conserved response to metabolic stress found in eukaryotes from yeast to mammals. it is noteworthy that autophagy is also associated with various pathophysiologic conditions in which this cellular process plays either a cytoprotective or cytopathic role in response to a variety of stresses such as metabolic, inflammatory, neuro ...201323943849
targeting antigens to dendritic cell receptors for vaccine development.dendritic cells (dcs) are highly specialized antigen presenting cells of the immune system which play a key role in regulating immune responses. depending on the method of antigen delivery, dcs stimulate immune responses or induce tolerance. as a consequence of the dual function of dcs, dcs are studied in the context of immunotherapy for both cancer and autoimmune diseases. in vaccine development, a major aim is to induce strong, specific t-cell responses. this is achieved by targeting antigen t ...201324228179
the role of b cells and humoral immunity in mycobacterium tuberculosis infection.tuberculosis (tb) remains a serious threat to public health, causing 2 million deaths annually world-wide. the control of tb has been hindered by the requirement of long duration of treatment involving multiple chemotherapeutic agents, the increased susceptibility to mycobacterium tuberculosis infection in the hiv-infected population, and the development of multi-drug resistant and extensively resistant strains of tubercle bacilli. an efficacious and cost-efficient way to control tb is the devel ...201323468112
intracellular pathogen detection by rig-i-like receptors.the rig-i-like receptors (rlrs) rig-i, mda5, and lgp2 trigger innate immune responses against viral infections that serve to limit virus replication and to stimulate adaptive immunity. rlrs are cytosolic sensors for virus-derived rna and thus responsible for intracellular immune surveillance against infection. rlr signaling requires the adapter protein mavs to induce type i interferon, interferon-stimulated genes, and proinflammatory cytokines. this review focuses on the molecular and cell biolo ...201323611287
prolonged polyarthralgia in a german traveller with mayaro virus infection without inflammatory correlates.mayaro virus is endemic in south america and sporadic outbreaks have been described. it causes a dengue-like febrile illness accompanied by severe and long-lasting polyarthralgias. outside endemic regions, however, the disease is not well known and can be misdiagnosed as dengue. international travellers are at risk to acquire mayaro virus and due to increased worldwide travel infectious disease specialists need to be aware of such rare clinical entities.201323927600
vector-borne disease intelligence: strategies to deal with disease burden and threats.owing to the complex nature of vector-borne diseases (vbds), whereby monitoring of human case patients does not suffice, public health authorities experience challenges in surveillance and control of vbds. knowledge on the presence and distribution of vectors and the pathogens that they transmit is vital to the risk assessment process to permit effective early warning, surveillance, and control of vbds. upon accepting this reality, public health authorities face an ever-increasing range of possi ...201425566522
climate change and infectious diseases in the arctic: establishment of a circumpolar working group.the arctic, even more so than other parts of the world, has warmed substantially over the past few decades. temperature and humidity influence the rate of development, survival and reproduction of pathogens and thus the incidence and prevalence of many infectious diseases. higher temperatures may also allow infected host species to survive winters in larger numbers, increase the population size and expand their habitat range. the impact of these changes on human disease in the arctic has not bee ...201425317383
pathogen inactivation technologies for cellular blood components: an update.nowadays patients receiving blood components are exposed to much less transfusion-transmitted infectious diseases than three decades before when among others hiv was identified as causative agent for the acquired immunodeficiency syndrome and the transmission by blood or coagulation factors became evident. since that time the implementation of measures for risk prevention and safety precaution was socially and politically accepted. currently emerging pathogens like arboviruses and the well-known ...201425254027
massive infection of seabird ticks with bacterial species related to coxiella burnetii.seabird ticks are known reservoirs of bacterial pathogens of medical importance; however, ticks parasitizing tropical seabirds have received less attention than their counterparts from temperate and subpolar regions. recently, rickettsia africae was described to infect seabird ticks of the western indian ocean and new caledonia, constituting the only available data on bacterial pathogens associated with tropical seabird tick species. here, we combined a pyrosequencing-based approach with a class ...201424657860
type-i interferons suppress microglial production of the lymphoid chemokine, cxcl13.lymphoid chemokines are crucial for the development and maintenance of lymphoid organs, but their ectopic expression in non-lymphoid tissues is implicated in both local response to infection and chronic organ-specific autoimmunity. production of one such chemokine, c-x-c motif ligand 13 (cxcl13), within the central nervous system (cns) has been linked to the pathogenesis of multiple sclerosis (ms), although little is known about factors controlling its expression in different neural cell types a ...201424829092
estimating the burden of japanese encephalitis virus and other encephalitides in countries of the mekong region.diverse aetiologies of viral and bacterial encephalitis are widely recognized as significant yet neglected public health issues in the mekong region. a robust analysis of the corresponding health burden is lacking. we retrieved 75 articles on encephalitis in the region published in english or in french from 1965 through 2011. review of available data demonstrated that they are sparse and often derived from hospital-based studies with significant recruitment bias. almost half (35 of 75) of articl ...201424498443
applications of in vivo imaging in the evaluation of the pathophysiology of viral and bacterial infections and in development of countermeasures to bsl3/4 pathogens.while preclinical and clinical imaging have been applied to drug discovery/development and characterization of disease pathology, few examples exist where imaging has been used to evaluate infectious agents or countermeasures to biosafety level (bsl)3/4 threat agents. viruses engineered with reporter constructs, i.e., enzymes and receptors, which are amenable to detection by positron emission tomography (pet), single photon emission tomography (spect), or magnetic resonance imaging (mri) have be ...201425008802
human pathogenic bacteria, fungi, and viruses in drosophila: disease modeling, lessons, and shortcomings.drosophila has been the invertebrate model organism of choice for the study of innate immune responses during the past few decades. many drosophila-microbe interaction studies have helped to define innate immunity pathways, and significant effort has been made lately to decipher mechanisms of microbial pathogenesis. here we catalog 68 bacterial, fungal, and viral species studied in flies, 43 of which are relevant to human health. we discuss studies of human pathogens in flies revealing not only ...201424398387
identification of the catalytic triad of family s46 exopeptidases, closely related to clan pa endopeptidases.the exopeptidases of family s46 are exceptional, as the closest homologs of these enzymes are the endopeptidases of clan pa. the three-dimensional structure of s46 enzymes is unknown and only one of the catalytic residues, the serine, has been identified. the catalytic histidine and aspartate residues are not experimentally identified. here we present phylogenetic and experimental data that identify all residues of the catalytic triad of s46 peptidase, dipeptidyl aminopeptidase bii (dap bii) fro ...201424598890
distribution of protein poly(adp-ribosyl)ation systems across all domains of life.poly(adp-ribosyl)ation is a post-translational modification of proteins involved in regulation of many cellular pathways. poly(adp-ribose) (par) consists of chains of repeating adp-ribose nucleotide units and is synthesized by the family of enzymes called poly(adp-ribose) polymerases (parps). this modification can be removed by the hydrolytic action of poly(adp-ribose) glycohydrolase (parg) and adp-ribosylhydrolase 3 (arh3). hydrolytic activity of macrodomain proteins (macrod1, macrod2 and targ1 ...201424865146
the role of b cells and humoral immunity in mycobacterium tuberculosis infection.mycobacterium tuberculosis remains a major public health burden. it is generally thought that while b cell- and antibody-mediated immunity plays an important role in host defense against extracellular pathogens, the primary control of intracellular microbes derives from cellular immune mechanisms. studies on the immune regulatory mechanisms during infection with m. tuberculosis, a facultative intracellular organism, has established the importance of cell-mediated immunity in host defense during ...201425458990
identification of sphingomyelinase on the surface of chlamydia pneumoniae: possible role in the entry into its host cells.we have recently suggested a novel mechanism, autoendocytosis, for the entry of certain microbes into their hosts, with a key role played by the sphingomyelinase-catalyzed topical conversion of sphingomyelin to ceramide, the differences in the biophysical properties of these two lipids providing the driving force. the only requirement for such microbes to utilize this mechanism is that they should have a catalytically active smase on their outer surface while the target cells should expose sphin ...201424757444
alphavirus-based vaccines.alphavirus vectors have demonstrated high levels of transient heterologous gene expression both in vitro and in vivo and, therefore, possess attractive features for vaccine development. the most commonly used delivery vectors are based on three single-stranded encapsulated alphaviruses, namely semliki forest virus, sindbis virus and venezuelan equine encephalitis virus. alphavirus vectors have been applied as replication-deficient recombinant viral particles and, more recently, as replication-pr ...201424937089
evolutionary genetics and vector adaptation of recombinant viruses of the western equine encephalitis antigenic complex provides new insights into alphavirus diversity and host switching.western equine encephalitis virus (weev), highlands j virus (hjv), and fort morgan virus (fmv) are the sole representatives of the wee antigenic complex of the genus alphavirus, family togaviridae, that are endemic to north america. all three viruses have their ancestry in a recombination event involving eastern equine encephalitis virus (eeev) and a sindbis (sin)-like virus that gave rise to a chimeric alphavirus that subsequently diversified into the present-day weev, hjv, and fmv. here, we pr ...201425463613
in- silico exploration of thirty alphavirus genomes for analysis of the simple sequence repeats.the compilation of simple sequence repeats (ssrs) in viruses and its analysis with reference to incidence, distribution and variation would be instrumental in understanding the functional and evolutionary aspects of repeat sequences. present study encompasses the analysis of ssrs across 30 species of alphaviruses. the full length genome sequences, assessed from ncbi were used for extraction and analysis of repeat sequences using imex software. the repeats of different motif sizes (mono- to penta ...201425606453
chikungunya fever in canada: fever and polyarthritis in a returned traveller. 201424566646
ccr2 deficiency promotes exacerbated chronic erosive neutrophil-dominated chikungunya virus arthritis.chikungunya virus (chikv) is a member of a globally distributed group of arthritogenic alphaviruses that cause weeks to months of debilitating polyarthritis/arthralgia, which is often poorly managed with current treatments. arthritic disease is usually characterized by high levels of the chemokine ccl2 and a prodigious monocyte/macrophage infiltrate. several inhibitors of ccl2 and its receptor ccr2 are in development and may find application for treatment of certain inflammatory conditions, incl ...201424696480
arthritogenic alphaviral infection perturbs osteoblast function and triggers pathologic bone loss.arthritogenic alphaviruses including ross river virus (rrv), sindbis virus, and chikungunya virus cause worldwide outbreaks of musculoskeletal disease. the ability of alphaviruses to induce bone pathologies remains poorly defined. here we show that primary human osteoblasts (hobs) can be productively infected by rrv. rrv-infected hobs produced high levels of inflammatory cytokine including il-6. the rankl/opg ratio was disrupted in the synovial fluid of rrv patients, and this was accompanied by ...201424733914
structural plasticity of the semliki forest virus glycome upon interspecies transmission.cross-species viral transmission subjects parent and progeny alphaviruses to differential post-translational processing of viral envelope glycoproteins. alphavirus biogenesis has been extensively studied, and the semliki forest virus e1 and e2 glycoproteins have been shown to exhibit differing degrees of processing of n-linked glycans. however the composition of these glycans, including that arising from different host cells, has not been determined. here we determined the chemical composition o ...201424467287
therapeutic vaccine strategies against human papillomavirus.high-risk types of human papillomavirus (hpv) cause over 500,000 cervical, anogenital and oropharyngeal cancer cases per year. the transforming potential of hpvs is mediated by viral oncoproteins. these are essential for the induction and maintenance of the malignant phenotype. thus, hpv-mediated malignancies pose the unique opportunity in cancer vaccination to target immunologically foreign epitopes. therapeutic hpv vaccination is therefore an ideal scenario for proof-of-concept studies of canc ...201426344626
salmonid alphavirus replication in mosquito cells: towards a novel vaccine production system.salmonid alphavirus (sav) causes pancreas disease and sleeping disease in atlantic salmon (salmo salar) and rainbow trout (oncorhynchus mykiss) and confers a major burden to the aquaculture industry. a commercial inactivated whole virus vaccine propagated in a salmon cell line at low temperature provides effective protection against sav infections. alphaviruses (family togaviridae) are generally transmitted between vertebrate hosts via blood-sucking arthropod vectors, typically mosquitoes. sav i ...201424418177
recent developments in preclinical dna vaccination.the advantages of genetic immunization of the new vaccine using plasmid dnas are multifold. for example, it is easy to generate plasmid dnas, increase their dose during the manufacturing process, and sterilize them. furthermore, they can be stored for a long period of time upon stabilization, and their protein encoding sequences can be easily modified by employing various dna-manipulation techniques. although dna vaccinations strongly increase th1-mediated immune responses in animals, several pr ...201426344468
a 6k-deletion variant of salmonid alphavirus is non-viable but can be rescued through rna recombination.pancreas disease (pd) of atlantic salmon is an emerging disease caused by salmonid alphavirus (sav) which mainly affects salmonid aquaculture in western europe. although genome structure of sav has been characterized and each individual viral protein has been identified, the role of 6k protein in viral replication and infectivity remains undefined. the 6k protein of alphaviruses is a small and hydrophobic protein which is involved in membrane permeabilization, protein processing and virus buddin ...201425009976
characterizing functional domains for tim-mediated enveloped virus entry.t-cell immunoglobulin and mucin domain 1 (tim-1) and other tim family members were recently identified as phosphatidylserine (ptdser)-mediated virus entry-enhancing receptors (pveers). these proteins enhance entry of ebola virus (ebov) and other viruses by binding ptdser on the viral envelope, concentrating virus on the cell surface, and promoting subsequent internalization. the ptdser-binding activity of the immunoglobulin-like variable (igv) domain is essential for both virus binding and inter ...201424696470
role of phosphatidylserine receptors in enveloped virus infection.we recently demonstrated that a soluble protein, gas6, can facilitate viral entry by bridging viral envelope phosphatidylserine to axl, a receptor tyrosine kinase expressed on target cells. the interaction between phosphatidylserine, gas6, and axl was originally shown to be a molecular mechanism through which phagocytes recognize phosphatidylserine exposed on dead cells. since our initial report, several groups have confirmed that axl/gas6, as well as other phosphatidylserine receptors, facilita ...201424478428
the c-terminal repeat domains of nsp3 from the old world alphaviruses bind directly to g3bp.the old world alphaviruses block stress granule assembly by sequestration of rasgap sh3-domain binding protein (g3bp). here, we show that the proline-rich sequences in the hypervariable domain of nonstructural protein 3 (nsp3) of both semliki forest virus and chikungunya virus were dispensable for binding to g3bp. nsp3 variants with or without this domain colocalized with g3bp. furthermore, we show that the c-terminal repeat motifs of nsp3 were sufficient for g3bp binding.201424623412
residue 82 of the chikungunya virus e2 attachment protein modulates viral dissemination and arthritis in mice.chikungunya virus (chikv) is a mosquito-borne alphavirus that has reemerged to cause profound epidemics of fever, rash, and arthralgia throughout sub-saharan africa, southeast asia, and the caribbean. like other arthritogenic alphaviruses, mechanisms of chikv pathogenesis are not well defined. using the attenuated chikv strain 181/25 and virulent strain af15561, we identified a residue in the e2 viral attachment protein that is a critical determinant of viral replication in cultured cells and pa ...201425142598
structural differences observed in arboviruses of the alphavirus and flavivirus genera.arthropod borne viruses have developed a complex life cycle adapted to alternate between insect and vertebrate hosts. these arthropod-borne viruses belong mainly to the families togaviridae, flaviviridae, and bunyaviridae. this group of viruses contains many pathogens that cause febrile, hemorrhagic, and encephalitic disease or arthritic symptoms which can be persistent. it has been appreciated for many years that these viruses were evolutionarily adapted to function in the highly divergent cell ...201425309597
the role of myeloid cell activation and arginine metabolism in the pathogenesis of virus-induced diseases.when an antiviral immune response is generated, a balance must be reached between two opposing pathways: the production of proinflammatory and cytotoxic effectors that drive a robust antiviral immune response to control the infection and regulators that function to limit or blunt an excessive immune response to minimize immune-mediated pathology and repair tissue damage. myeloid cells, including monocytes and macrophages, play an important role in this balance, particularly through the activitie ...201425250029
prime-boost immunization strategies against chikungunya virus.chikungunya virus (chikv) is a reemerging mosquito-borne alphavirus that causes debilitating arthralgia in humans. here we describe the development and testing of novel dna replicon and protein chikv vaccine candidates and evaluate their abilities to induce antigen-specific immune responses against chikv. we also describe homologous and heterologous prime-boost immunization strategies using novel and previously developed chikv vaccine candidates. immunogenicity and efficacy were studied in a mou ...201425210177
high efficiency of alphaviral gene transfer in combination with 5-fluorouracil in a mouse mammary tumor model.the combination of virotherapy and chemotherapy may enable efficient tumor regression that would be unachievable using either therapy alone. in this study, we investigated the efficiency of transgene delivery and the cytotoxic effects of alphaviral vector in combination with 5-fluorouracil (5-fu) in a mouse mammary tumor model (4 t1).201424950740
ebolavirus entry requires a compact hydrophobic fist at the tip of the fusion loop.ebolavirus is an enveloped virus causing severe hemorrhagic fever. its surface glycoproteins undergo proteolytic cleavage and rearrangements to permit membrane fusion and cell entry. here we focus on the glycoprotein's internal fusion loop (fl), critical for low-ph-triggered fusion in the endosome. alanine mutations at l529 and i544 and particularly the l529 i544 double mutation compromised viral entry and fusion. the nuclear magnetic resonance (nmr) structures of the i544a and l529a i544a mutan ...201424696482
exploration of panviral proteome: high-throughput cloning and functional implications in virus-host interactions.throughout the long history of virus-host co-evolution, viruses have developed delicate strategies to facilitate their invasion and replication of their genome, while silencing the host immune responses through various mechanisms. the systematic characterization of viral protein-host interactions would yield invaluable information in the understanding of viral invasion/evasion, diagnosis and therapeutic treatment of a viral infection, and mechanisms of host biology. with more than 2,000 viral ge ...201424955142
locking and blocking the viral landscape of an alphavirus with neutralizing antibodies.alphaviruses are serious, sometimes lethal human pathogens that belong to the family togaviridae. the structures of human venezuelan equine encephalitis virus (veev), an alphavirus, in complex with two strongly neutralizing antibody fab fragments (f5 and 3b4c-4) have been determined using a combination of cryo-electron microscopy and homology modeling. we characterize these monoclonal antibody fab fragments, which are known to abrogate veev infectivity by binding to the e2 (envelope) surface gly ...201424920796
expanding the proteome of an rna virus by phosphorylation of an intrinsically disordered viral protein.the human proteome contains myriad intrinsically disordered proteins. within intrinsically disordered proteins, polyproline-ii motifs are often located near sites of phosphorylation. we have used an unconventional experimental paradigm to discover that phosphorylation by protein kinase a (pka) occurs in the intrinsically disordered domain of hepatitis c virus non-structural protein 5a (ns5a) on thr-2332 near one of its polyproline-ii motifs. phosphorylation shifts the conformational ensemble of ...201425031324
a small molecule inhibits virion attachment to heparan sulfate- or sialic acid-containing glycans.primary attachment to cellular glycans is a critical entry step for most human viruses. some viruses, such as herpes simplex virus type 1 (hsv-1) and hepatitis c virus (hcv), bind to heparan sulfate, whereas others, such as influenza a virus (iav), bind to sialic acid. receptor mimetics that interfere with these interactions are active against viruses that bind to either heparan sulfate or to sialic acid. however, no molecule that inhibits the attachment of viruses in both groups has yet been id ...201424789779
mutations conferring a noncytotoxic phenotype on chikungunya virus replicons compromise enzymatic properties of nonstructural protein 2.chikungunya virus (chikv) (genus alphavirus) has a positive-sense rna genome. chikv nonstructural protein 2 (nsp2) proteolytically processes the viral nonstructural polyprotein, possesses nucleoside triphosphatase (ntpase), rna triphosphatase, and rna helicase activities, and induces cytopathic effects in vertebrate cells. although alphaviral nsp2 mutations can result in a noncytotoxic phenotype, the effects of such mutations on nsp2 enzymatic activities are not well understood. in this study, w ...201425552719
emerging roles of interferon-stimulated genes in the innate immune response to hepatitis c virus infection.infection with hepatitis c virus (hcv), a major viral cause of chronic liver disease, frequently progresses to steatosis and cirrhosis, which can lead to hepatocellular carcinoma. hcv infection strongly induces host responses, such as the activation of the unfolded protein response, autophagy and the innate immune response. upon hcv infection, the host induces the interferon (ifn)-mediated frontline defense to limit virus replication. conversely, hcv employs diverse strategies to escape host inn ...201425544499
trans-protease activity and structural insights into the active form of the alphavirus capsid protease.the alphavirus capsid protein (cp) is a serine protease that possesses cis-proteolytic activity essential for its release from the nascent structural polyprotein. the released cp further participates in viral genome encapsidation and nucleocapsid core formation, followed by its attachment to glycoproteins and virus budding. thus, protease activity of the alphavirus capsid is a potential antialphaviral target to arrest capsid release, maturation, and structural polyprotein processing. however, th ...201425100849
screening and large-scale expression of membrane proteins in mammalian cells for structural studies.structural, biochemical and biophysical studies of eukaryotic membrane proteins are often hampered by difficulties in overexpression of the candidate molecule. baculovirus transduction of mammalian cells (bacmam), although a powerful method to heterologously express membrane proteins, can be cumbersome for screening and expression of multiple constructs. we therefore developed plasmid eric gouaux (peg) bacmam, a vector optimized for use in screening assays, as well as for efficient production of ...201425299155
identification and characterization of alphavirus m1 as a selective oncolytic virus targeting zap-defective human cancers.oncolytic virotherapy is a growing treatment modality that uses replicating viruses as selective antineoplastic agents. safety and efficacy considerations dictate that an ideal oncolytic agent would discriminate between normal and cancer cells on the basis of common genetic abnormalities in human cancers. here, we identify a naturally occurring alphavirus (m1) as a novel selective killer targeting zinc-finger antiviral protein (zap)-deficient cancer cells. in vitro, in vivo, and ex vivo studies ...201425288727
novel indole-2-carboxamide compounds are potent broad-spectrum antivirals active against western equine encephalitis virus in vivo.neurotropic alphaviruses, including western, eastern, and venezuelan equine encephalitis viruses, cause serious and potentially fatal central nervous system infections in humans for which no currently approved therapies exist. we previously identified a series of thieno[3,2-b]pyrrole derivatives as novel inhibitors of neurotropic alphavirus replication, using a cell-based phenotypic assay (w. peng et al., j. infect. dis. 199:950-957, 2009, doi:http://dx.doi.org/10.1086/597275), and subsequently ...201425031353
the composition of west nile virus lipid envelope unveils a role of sphingolipid metabolism in flavivirus biogenesis.west nile virus (wnv) is an emerging zoonotic mosquito-borne flavivirus responsible for outbreaks of febrile illness and meningoencephalitis. the replication of wnv takes place on virus-modified membranes from the endoplasmic reticulum of the host cell, and virions acquire their envelope by budding into this organelle. consistent with this view, the cellular biology of this pathogen is intimately linked to modifications of the intracellular membranes, and the requirement for specific lipids, suc ...201425122799
initiation codon selection is accomplished by a scanning mechanism without crucial initiation factors in sindbis virus subgenomic mrna.translation initiation of alphavirus subgenomic mrna (sgmrna) can occur in the absence of several initiation factors (eifs) in infected cells; however, the precise translation mechanism is still poorly understood. in this study, we have examined the mechanism of initiation and aug selection in sindbis virus (sinv) sgmrna. our present findings suggest that sgmrna is translated via a scanning mechanism, since the presence of a hairpin structure before the initiation codon hampers protein synthesis ...201425404563
role of micrornas in arbovirus/vector interactions.the role of micrornas (mirnas) as small non-coding rnas in regulation of gene expression has been recognized. they appear to be involved in regulation of a wide range of cellular pathways that affect several biological processes such as development, the immune system, survival, metabolism and host-pathogen interactions. arthropod-borne viruses impose great economic and health risks around the world. recent advances in mirna biology have shed some light on the role of these small rnas in vector-v ...201425251636
antiviral responses of arthropod vectors: an update on recent advances.arthropod vectors, such as mosquitoes, ticks, biting midges and sand flies, transmit many viruses that can cause outbreaks of disease in humans and animals around the world. arthropod vector species are invading new areas due to globalisation and environmental changes, and contact between exotic animal species, humans and arthropod vectors is increasing, bringing with it the regular emergence of new arboviruses. for future strategies to control arbovirus transmission, it is important to improve ...201425674592
an alphavirus-based adjuvant enhances serum and mucosal antibodies, t cells, and protective immunity to influenza virus in neonatal mice.neonatal immune responses to infection and vaccination are biased toward th2 at the cost of proinflammatory th1 responses needed to combat intracellular pathogens. however, upon appropriate stimulation, the neonatal immune system can induce adult-like th1 responses. here we report that a new class of vaccine adjuvant is especially well suited to enhance early life immunity. the gvi3000 adjuvant is a safe, nonpropagating, truncated derivative of venezuelan equine encephalitis virus that targets d ...201424899195
characterization of aedes aegypti innate-immune pathways that limit chikungunya virus replication.replication of arboviruses in their arthropod vectors is controlled by innate immune responses. the rna sequence-specific break down mechanism, rna interference (rnai), has been shown to be an important innate antiviral response in mosquitoes. in addition, immune signaling pathways have been reported to mediate arbovirus infections in mosquitoes; namely the jak/stat, immune deficiency (imd) and toll pathways. very little is known about these pathways in response to chikungunya virus (chikv) infe ...201425058001
heparan sulfate proteoglycan: an arbovirus attachment factor integral to mosquito salivary gland ducts.variants of the prototype alphavirus, sindbis (sinv), were used in per os infections of adult female mosquitoes to investigate arbovirus interaction with the salivary gland (sg). infection of aedine mosquitoes with ar339, a heparan sulfate proteoglycan (hspg)-dependent variant, resulted in gross pathology in the sg lateral lobes while infection with tr339, a hspg-independent variant, resulted in minimal sg pathology. hspg was detected in the internal ducts of the sg lateral lobes by immunolabeli ...201425533661
repertoire of virus-derived small rnas produced by mosquito and mammalian cells in response to dengue virus infection.rna interference (rnai) is the major defense of many arthropods against arthropod-borne rna viruses (arboviruses), but the role of rnai in vertebrate immunity to arboviruses is not clear. rna viruses can trigger rnai in vertebrate cells, but the vertebrate interferon response may obscure this interaction. we quantified virus-derived small rnas (vrnas) generated by mosquito (u4.4) cells and interferon-deficient (vero) and interferon-competent (huh-7) mammalian cells infected with a single isolate ...201425528416
ph-dependent entry of chikungunya virus fusion into mosquito cells.millions of human infections caused by arthropod-borne pathogens are initiated by the feeding of an infected mosquito on a vertebrate. however, interactions between the viruses and the mosquito vector, which facilitates successful infection and transmission of virus to a subsequent vertebrate host, are still not fully understood.201425476236
host control of insect endogenous retroviruses: small rna silencing and immune response.endogenous retroviruses are relics of ancient infections from retroviruses that managed to integrate into the genome of germline cells and remained vertically transmitted from parent to progeny. subsequent to the endogenization process, these sequences can move and multiply in the host genome, which can have deleterious consequences and disturb genomic stability. natural selection favored the establishment of silencing pathways that protect host genomes from the activity of endogenous retrovirus ...201425412365
gas chromatography-mass spectroscopy analysis of bioactive petalostigma extracts: toxicity, antibacterial and antiviral activities.petalostigma pubescens and petalostigma triloculare were common components of pharmacopeia's of multiple australian aboriginal tribal groupings which traditionally inhabited the areas in which they grow. among these groups, they had a myriad of medicinal uses in treating a wide variety of bacterial, fungal and viral infections. this study was undertaken to test p. pubescens and p. triloculare leaf and fruit extracts for the ability to inhibit bacterial and viral growth and thus validate australi ...201424914307
eilat virus host range restriction is present at multiple levels of the virus life cycle.most alphaviruses are mosquito-borne and exhibit a broad host range, infecting many different vertebrates, including birds, rodents, equids, humans, and nonhuman primates. this ability of most alphaviruses to infect arthropods and vertebrates is essential for their maintenance in nature. recently, a new alphavirus, eilat virus (eilv), was described, and in contrast to all other mosquito-borne viruses, it is unable to replicate in vertebrate cell lines. investigations into the nature of its host ...201425392227
chemokine receptors as important regulators of pathogenesis during arboviral encephalitis.the central nervous system (cns) is a highly complex network comprising long-lived neurons and glial cells. accordingly, numerous mechanisms have evolved to tightly regulate the initiation of inflammatory responses within the brain. under neuroinflammatory conditions, as in the case of viral encephalitides, the infiltration of leukocytes is often required for efficient viral clearance and recovery. the orchestration of leukocyte migration into the inflamed cns is largely coordinated by a large f ...201425324719
mosquito cell lines: history, isolation, availability and application to assess the threat of arboviral transmission in the united kingdom.mosquitoes are highly effective vectors for transmission of human and animal pathogens. understanding the relationship between pathogen and vector is vital in developing strategies to predict and prevent transmission. cell lines derived from appropriate mosquito hosts provide a relatively simple tool for investigating the interaction between the host and viruses transmitted by mosquitoes. this review provides a brief overview of the development of mosquito cell lines, methods of isolation, their ...201425141888
second generation inactivated eastern equine encephalitis virus vaccine candidates protect mice against a lethal aerosol challenge.currently, there are no fda-licensed vaccines or therapeutics for eastern equine encephalitis virus (eeev) for human use. we recently developed several methods to inactivate cvev1219, a chimeric live-attenuated eastern equine encephalitis virus (eeev). dosage and schedule studies were conducted to evaluate the immunogenicity and protective efficacy of three potential second-generation inactivated eeev (ieeev) vaccine candidates in mice: formalin-inactivated cvev1219 (fcvev1219), ina-inactivated ...201425116127
human trophoblasts confer resistance to viruses implicated in perinatal infection.primary human trophoblasts were previously shown to be resistant to viral infection, and able to confer this resistance to nontrophoblast cells. can trophoblasts protect nontrophoblastic cells from infection by viruses or other intracellular pathogens that are implicated in perinatal infection?201425108145
dominance effects of deleterious and beneficial mutations in a single gene of the rna virus ϕ6.most of our knowledge of dominance stems from studies of deleterious mutations. from these studies we know that most deleterious mutations are recessive, and that this recessivity arises from a hyperbolic relationship between protein function (i.e., protein concentration or activity) and fitness. here we investigate whether this knowledge can be used to make predictions about the dominance of beneficial and deleterious mutations in a single gene. we employed a model system--the bacteriophage φ6- ...201424945910
discovery of a novel compound with anti-venezuelan equine encephalitis virus activity that targets the nonstructural protein 2.alphaviruses present serious health threats as emerging and re-emerging viruses. venezuelan equine encephalitis virus (veev), a new world alphavirus, can cause encephalitis in humans and horses, but there are no therapeutics for treatment. to date, compounds reported as anti-veev or anti-alphavirus inhibitors have shown moderate activity. to discover new classes of anti-veev inhibitors with novel viral targets, we used a high-throughput screen based on the measurement of cell protection from liv ...201424967809
human-like antibodies neutralizing western equine encephalitis virus.this study describes the development of the first neutralizing antibodies against western equine encephalitis virus (weev), a member of the genus alphavirus. weev is transmitted by mosquitoes and can spread to the human central nervous system, causing symptoms ranging from mild febrile reactions to life-threatening encephalitis. weev has been classified as a biological warfare agent by the us centers for disease control and prevention. no anti-weev drugs are currently commercially available. neu ...201424518197
molecular evolutionary and epidemiological dynamics of genotypes 1g and 2b of rubella virus.rubella virus (rv), which causes measles-like rashes in children, puts millions of infants at risk of congenital defects across the globe. employing phylogenetic approaches to the whole genome sequence data and e1 glycoprotein sequence data, the present study reports the substitution rates and dates of emergence of all thirteen previously described rubella genotypes, and gains important insights into the epidemiological dynamics of two geographically widely distributed genotypes 1g and 2b. the o ...201425329480
replication of many human viruses is refractory to inhibition by endogenous cellular micrornas.the issue of whether viruses are subject to restriction by endogenous micrornas (mirnas) and/or by virus-induced small interfering rnas (sirnas) in infected human somatic cells has been controversial. here, we address this question in two ways. first, using deep sequencing, we demonstrate that infection of human cells by the rna virus dengue virus (denv) or west nile virus (wnv) does not result in the production of any virus-derived sirnas or viral mirnas. second, to more globally assess the pot ...201424807715
functional cross-talk between distant domains of chikungunya virus non-structural protein 2 is decisive for its rna-modulating activity.chikungunya virus (chikv) non-structural protein 2 (nsp2) is a multifunctional protein that is considered a master regulator of the viral life cycle and a main viral factor responsible for cytopathic effects and subversion of antiviral defense. the c-terminal part of nsp2 possesses protease activity, whereas the n-terminal part exhibits ntpase and rna triphosphatase activity and is proposed to have helicase activity. bioinformatics analysis classified chikv nsp2 into helicase superfamily 1. howe ...201424407286
immunologic treatments for precancerous lesions and uterine cervical cancer.development of hpv-associated cancers not only depends on efficient negative regulation of cell cycle control that supports the accumulation of genetic damage, but also relies on immune evasion that enable the virus to go undetected for long periods of time. in this way, hpv-related tumors usually present mhc class i down-regulation, impaired antigen-processing ability, avoidance of t-cell mediated killing, increased immunosuppression due to treg infiltration and secrete immunosuppressive cytoki ...201424667138
buggy creek virus (togaviridae: alphavirus) upregulates expression of pattern recognition receptors and interferons in house sparrows (passer domesticus).birds serve as reservoirs for at least 10 arthropod-borne viruses, yet specific immune responses of birds to arboviral infections are relatively unknown. here, adult house sparrows were inoculated with an arboviral alphavirus, buggy creek virus (bcrv), or saline, and euthanized between 1 and 3 days postinoculation. virological dynamics and gene expression dynamics were investigated. birds did not develop viremia postinoculation, but cytopathic virus was found in the skeletal muscle and spleen of ...201424866749
antiviral perspectives for chikungunya virus.chikungunya virus (chikv) is a mosquito-borne pathogen that has a major health impact in humans and causes acute febrile illness in humans accompanied by joint pains and, in many cases, persistent arthralgia lasting for weeks to years. chikv reemerged in 2005-2006 in several parts of the indian ocean islands and india after a gap of 32 years, causing millions of cases. the re-emergence of chikv has also resulted in numerous outbreaks in several countries in the eastern hemisphere, with a threat ...201424955364
inhibition of acid sphingomyelinase by tricyclic antidepressants and analogons.amitriptyline, a tricyclic antidepressant, has been used in the clinic to treat a number of disorders, in particular major depression and neuropathic pain. in the 1970s the ability of tricyclic antidepressants to inhibit acid sphingomyelinase (asm) was discovered. the enzyme asm catalyzes the hydrolysis of sphingomyelin to ceramide. asm and ceramide were shown to play a crucial role in a wide range of diseases, including cancer, cystic fibrosis, diabetes, alzheimer's disease, and major depressio ...201425228885
bindarit, an inhibitor of monocyte chemotactic protein synthesis, protects against bone loss induced by chikungunya virus infection.the recent global resurgence of arthritogenic alphaviruses, in particular chikungunya virus (chikv), highlights an urgent need for the development of therapeutic intervention strategies. while there has been significant progress in defining the pathophysiology of alphaviral disease, relatively little is known about the mechanisms involved in chikv-induced arthritis or potential therapeutic options to treat the severe arthritic symptoms associated with infection. here, we used microcomputed tomog ...201425339772
pathogen-inspired drug delivery to the central nervous system.for as long as the human blood-brain barrier (bbb) has been evolving to exclude bloodborne agents from the central nervous system (cns), pathogens have adopted a multitude of strategies to bypass it. some pathogens, notably viruses and certain bacteria, enter the cns in whole form, achieving direct physical passage through endothelial or neuronal cells to infect the brain. other pathogens, including bacteria and multicellular eukaryotic organisms, secrete toxins that preferentially interact with ...201425610755
evidence of experimental vertical transmission of emerging novel ecsa genotype of chikungunya virus in aedes aegypti.chikungunya virus (chikv) has emerged as one of the most important arboviruses of public health significance in the past decade. the virus is mainly maintained through human-mosquito-human cycle. other routes of transmission and the mechanism of maintenance of the virus in nature are not clearly known. vertical transmission may be a mechanism of sustaining the virus during inter-epidemic periods. laboratory experiments were conducted to determine whether aedes aegypti, a principal vector, is cap ...201425080107
jatropha gossypiifolia l. (euphorbiaceae): a review of traditional uses, phytochemistry, pharmacology, and toxicology of this medicinal plant.jatropha gossypiifolia l. (euphorbiaceae), widely known as "bellyache bush," is a medicinal plant largely used throughout africa and america. several human and veterinary uses in traditional medicine are described for different parts and preparations based on this plant. however, critical reviews discussing emphatically its medicinal value are missing. this review aims to provide an up-to-date overview of the traditional uses, as well as the phytochemistry, pharmacology, and toxicity data of j. ...201425002902
multiple immune factors are involved in controlling acute and chronic chikungunya virus infection.the recent epidemic of the arthritogenic alphavirus, chikungunya virus (chikv) has prompted a quest to understand the correlates of protection against virus and disease in order to inform development of new interventions. herein we highlight the propensity of chikv infections to persist long term, both as persistent, steady-state, viraemias in multiple b cell deficient mouse strains, and as persistent rna (including negative-strand rna) in wild-type mice. the knockout mouse studies provided evid ...201425474568
exposure of epitope residues on the outer face of the chikungunya virus envelope trimer determines antibody neutralizing efficacy.chikungunya virus (chikv) is a reemerging alphavirus that causes a debilitating arthritic disease and infects millions of people and for which no specific treatment is available. like many alphaviruses, the structural targets on chikv that elicit a protective humoral immune response in humans are poorly defined. here we used phage display against virus-like particles (vlps) to isolate seven human monoclonal antibodies (mabs) against the chikv envelope glycoproteins e2 and e1. one mab, im-ckv063, ...201425275138
manipulation of host factors optimizes the pathogenesis of western equine encephalitis virus infections in mice for antiviral drug development.while alphaviruses spread naturally via mosquito vectors, some can also be transmitted as aerosols making them potential bioterrorism agents. one such pathogen, western equine encephalitis virus (weev), causes fatal human encephalitis via multiple routes of infection and thus presumably via multiple mechanisms. although weev also produces acute encephalitis in non-human primates, a small animal model that recapitulates features of human disease would be useful for both pathogenesis studies and t ...201425361697
enhanced production of chikungunya virus-like particles using a high-ph adapted spodoptera frugiperda insect cell line.chikungunya virus-like particles (vlps) have potential to be used as a prophylactic vaccine based on testing in multiple animal models and are currently being evaluated for human use in a phase i clinical trial. the current method for producing these enveloped alphavirus vlps by transient gene expression in mammalian cells presents challenges for scalable and robust industrial manufacturing, so the insect cell baculovirus expression vector system was evaluated as an alternative expression techno ...201424713807
interferon-stimulated genes: roles in viral pathogenesis.interferon-stimulated genes (isgs) are critical for controlling virus infections. as new antiviral isgs continue to be identified and characterized, their roles in viral pathogenesis are also being explored in more detail. our current understanding of how isgs impact viral pathogenesis comes largely from studies in knockout mice, with isolated examples from human clinical data. this review outlines recent developments on the contributions of various isgs to viral disease outcomes in vivo.201424713352
enhancement of antitumor immunity using a dna-based replicon vaccine derived from semliki forest virus.a dna-based replicon vaccine derived from semliki forest virus, psvk-shfcg-gm/b7.1 (fig. 1a) was designed for tumor immunotherapy as previously constructed. the expression of the fusion tumor antigen (survivin and hcgβ-ctp37) and adjuvant molecular protein (granulocyte-macrophage colony-stimulating factor/ gm-csf/b7.1) genes was confirmed by immunofluorescence assay in vitro, and immunohistochemistry assay in vivo. in this paper, the immunological effect of this vaccine was determined using immu ...201424608380
relating structure to evolution in class ii viral membrane fusion proteins.enveloped viruses must fuse their lipid membrane to a cellular membrane to deliver the viral genome into the cytoplasm for replication. viral envelope proteins catalyze this critical membrane fusion event. they fall into at least three distinct structural classes. class ii fusion proteins have a conserved three-domain architecture and are found in many important viral pathogens. until 2013, class ii proteins had only been found in flaviviruses and alphaviruses. however, in 2013 a class ii fusion ...201424525225
regulation of the hepatitis c virus rna replicase by endogenous lipid peroxidation.oxidative tissue injury often accompanies viral infection, yet there is little understanding of how it influences virus replication. we show that multiple hepatitis c virus (hcv) genotypes are exquisitely sensitive to oxidative membrane damage, a property distinguishing them from other pathogenic rna viruses. lipid peroxidation, regulated in part through sphingosine kinase-2, severely restricts hcv replication in huh-7 cells and primary human hepatoblasts. endogenous oxidative membrane damage lo ...201425064127
attenuating mutations in nsp1 reveal tissue-specific mechanisms for control of ross river virus infection.ross river virus (rrv) is one of a group of mosquito-transmitted alphaviruses that cause debilitating, and often chronic, musculoskeletal disease in humans. previously, we reported that replacement of the nonstructural protein 1 (nsp1) gene of the mouse-virulent rrv strain t48 with that from the mouse-avirulent strain dc5692 generated a virus that was attenuated in a mouse model of disease. here we find that the six nsp1 nonsynonymous nucleotide differences between strains t48 and dc5692 are det ...201424429363
unfolded protein response in hepatitis c virus infection.hepatitis c virus (hcv) is a single-stranded, positive-sense rna virus of clinical importance. the virus establishes a chronic infection and can progress from chronic hepatitis, steatosis to fibrosis, cirrhosis, and hepatocellular carcinoma (hcc). the mechanisms of viral persistence and pathogenesis are poorly understood. recently the unfolded protein response (upr), a cellular homeostatic response to endoplasmic reticulum (er) stress, has emerged to be a major contributing factor in many human ...201424904547
efficient transfection of dissociated mouse chromaffin cells using small-volume electroporation.we have developed an improved procedure for isolating and transfecting a chromaffin cell-enriched population of primary cells from adult mouse adrenal glands. significantly, the parameters of a novel electroporation transfection technique were optimized to achieve an average transfection efficiency of 45 % on the small number of cells derived from the mouse glands. such transfection efficiency was previously unachievable with the electroporation protocols conventionally used with bovine chromaff ...201424549789
the major cellular sterol regulatory pathway is required for andes virus infection.the bunyaviridae comprise a large family of rna viruses with worldwide distribution and includes the pathogenic new world hantavirus, andes virus (andv). host factors needed for hantavirus entry remain largely enigmatic and therapeutics are unavailable. to identify cellular requirements for andv infection, we performed two parallel genetic screens. analysis of a large library of insertionally mutagenized human haploid cells and a sirna genomic screen converged on components (srebp-2, scap, s1p a ...201424516383
cd8+ t cells control ross river virus infection in musculoskeletal tissues of infected mice.ross river virus (rrv), chikungunya virus, and related alphaviruses cause debilitating polyarthralgia and myalgia. mouse models of rrv and chikungunya virus have demonstrated a role for the adaptive immune response in the control of these infections. however, questions remain regarding the role for t cells in viral control, including the magnitude, location, and dynamics of cd8(+) t cell responses. to address these questions, we generated a recombinant rrv expressing the h-2(b)-restricted glycop ...201425488988
two alternative ways of start site selection in human norovirus reinitiation of translation.the calicivirus minor capsid protein vp2 is expressed via termination/reinitiation. this process depends on an upstream sequence element denoted termination upstream ribosomal binding site (turbs). we have shown for feline calicivirus and rabbit hemorrhagic disease virus that the turbs contains three sequence motifs essential for reinitiation. motif 1 is conserved among caliciviruses and is complementary to a sequence in the 18 s rrna leading to the model that hybridization between motif 1 and 1 ...201424599949
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