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sphingolipids in viral infection.viruses exploit membranes and their components such as sphingolipids in all steps of their life cycle including attachment and membrane fusion, intracellular transport, replication, protein sorting and budding. examples for sphingolipid-dependent virus entry are found for: human immunodeficiency virus (hiv), which besides its protein receptors also interacts with glycosphingolipids (gsls); rhinovirus, which promotes the formation of ceramide-enriched platforms and endocytosis; or measles virus ( ...201525525752
oxidative stress influences positive strand rna virus genome synthesis and capping.flaviviruses are 5' capped positive-stranded rna viruses that replicate their genomes within endoplasmic reticulum-derived vesicles. flaviviruses are well known to induce oxidative stress late in infection but it is unknown if oxidative stress plays a positive role in the viral rna replication cycle. we therefore examined how oxidation affects flavivirus rna replication. we found that antioxidant treatment reduced virus production, reduced the viral positive-to-negative strand rna ratio, and res ...201425514423
synaptic strength is bidirectionally controlled by opposing activity-dependent regulation of nedd4-1 and usp8.the trafficking of ampa receptors (ampars) to and from synapses is crucial for synaptic plasticity. previous work has demonstrated that ampars undergo activity-dependent ubiquitination by the e3 ubiquitin ligase nedd4-1, which promotes their internalization and degradation in lysosomes. here, we define the molecular mechanisms involved in ubiquitination and deubiquitination of ampars. we report that nedd4-1 is rapidly redistributed to dendritic spines in response to ampar activation and not in r ...025505317
capacity of mosquitoes to transmit malaria depends on larval environment.adult traits of holometabolous insects such as reproduction and survival can be shaped by conditions experienced during larval development. these "carry-over" effects influence not only individual life history and fitness, but can also impact interactions between insect hosts and parasites. despite this, the implications of larval conditions for the transmission of human, wildlife and plant diseases that are vectored by insects remain poorly understood.201425496502
ddx17: structured rna recognition drives diverse outputs. 025493410
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
mining the human autoantibody repertoire: isolation of potent il17a-neutralizing monoclonal antibodies from a patient with thymoma.anti-cytokine autoantibodies have been widely reported to be present in human plasma, both in healthy subjects and in patients with underlying autoimmune conditions, such as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (apeced) or thymic epithelial neoplasms. while often asymptomatic, they can cause or facilitate a wide range of diseases including opportunistic infections. the potential therapeutic value of specific neutralizing anti-cytokine autoantibodies has not been thoroug ...025484038
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
pick1 links ampa receptor stimulation to cdc42.rho-family gtpases control numerous cell biological processes via effects on actin dynamics, such as cell migration, cell adhesion, morphogenesis and vesicle traffic. in neurons, they are involved in dendritic spine morphogenesis and other aspects of neuronal morphology via regulation of the actin cytoskeleton. the rho-family member cdc42 regulates dendritic spine morphology via its effector n-wasp, which activates the actin-nucleating arp2/3 complex. excitatory synaptic transmission is known to ...201425475687
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
the toll-dorsal pathway is required for resistance to viral oral infection in drosophila.pathogen entry route can have a strong impact on the result of microbial infections in different hosts, including insects. drosophila melanogaster has been a successful model system to study the immune response to systemic viral infection. here we investigate the role of the toll pathway in resistance to oral viral infection in d. melanogaster. we show that several toll pathway components, including spätzle, toll, pelle and the nf-kb-like transcription factor dorsal, are required to resist oral ...201425473839
mosquitoes (diptera: culicidae) and their relevance as disease vectors in the city of vienna, austria.mosquitoes (diptera: culicidae) are important vectors for a wide range of pathogenic organisms. as large parts of the human population in developed countries live in cities, the occurrence of vector-borne diseases in urban areas is of particular interest for epidemiologists and public health authorities. in this study, we investigated the mosquito occurrence in the city of vienna, austria, in order to estimate the risk of transmission of mosquito-borne diseases. mosquitoes were captured using di ...201425468380
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
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
a substitution in nsp1 combined with a double substitution in e2 glycoprotein renders sindbis-like virus xj-160 fully neurovirulent for adult mice.sindbis virus (sv) can be rendered neurovirulent for adult mice by a double substitution within the e2 glycoprotein, including replacing gln at position 55 of e2 with a his (e2-55: gln-his) and e2-70: glu to lys. however, the mutant sindbis-like virus xj-160 with the double substitution (br-e5570) does not show neurovirulence for adult mice, although the mutant apparently reduced the average survival time of neonatal mice. to produce an xj-160 virus neurovirulent for adult mice, the br-e5570 vir ...201525449361
response to voinnet et al. 025437535
organ-specific protective role of nkt cells in virus-induced inflammatory demyelination and myocarditis depends on mouse strain.theiler's murine encephalomyelitis virus (tmev) can induce demyelination or myocarditis in susceptible mouse strains. a deficiency of nkt cells exacerbated tmev-induced demyelinating disease (tmev-idd) in sjl/j and balb/c mice. in c57bl/6 background, however, nkt-cell-deficient jα18 ko mice remained as resistant to tmev-idd as wild-type mice. echocardiography and histology showed that jα18 ko mice developed more severe myocarditis (greater t cell infiltration and fibrosis) than wild-type mice, s ...201425434008
immune responses to non-tumor antigens in the central nervous system.the central nervous system (cns), once viewed as an immune-privileged site protected by the blood-brain barrier (bbb), is now known to be a dynamic immunological environment through which immune cells migrate to prevent and respond to events such as localized infection. during these responses, endogenous glial cells, including astrocytes and microglia, become highly reactive and may secrete inflammatory mediators that regulate bbb permeability and recruit additional circulating immune cells. her ...201425431758
interferon-stimulated gene 15 (isg15) and isg15-linked proteins can associate with members of the selective autophagic process, histone deacetylase 6 (hdac6) and sqstm1/p62.the ubiquitin-like interferon (ifn)-stimulated gene 15 (isg15) and its specific e1, e2, and e3 enzymes are transcriptionally induced by type i ifns. isg15 conjugates newly synthesized proteins. isg15 linkage to proteins appears to be an important downstream ifn signaling event that discriminates cellular and pathogenic proteins synthesized during ifn stimulation from existing proteins. this eliminates potentially pathogenic proteins as the cell attempts to return to normal homeostasis after ifn ...201425429107
interferon-induced ifit proteins: their role in viral pathogenesis.a major component of the protective antiviral host defense is contributed by the intracellular actions of the proteins encoded by interferon-stimulated genes (isgs); among these are the interferon-induced proteins with tetratricopeptide repeats (ifits), consisting of four members in human and three in mouse. ifit proteins do not have any known enzyme activity. instead, they inhibit virus replication by binding and regulating the functions of cellular and viral proteins and rnas. although all ifi ...201425428874
the nsp3 macrodomain promotes virulence in mice with coronavirus-induced encephalitis.all coronaviruses encode a macrodomain containing adp-ribose-1"-phosphatase (adrp) activity within the n terminus of nonstructural protein 3 (nsp3). previous work showed that mouse hepatitis virus strain a59 (mhv-a59) with a mutated catalytic site (n1348a) replicated similarly to wild-type virus but was unable to cause acute hepatitis in mice. to determine whether this attenuated phenotype is applicable to multiple disease models, we mutated the catalytic residue in the jhm strain of mhv (jhmv), ...201425428866
going viral and the fatal vulnerability of neurons from immunity, not from infection. 201425422437
emerging biomedical applications of nano-chitins and nano-chitosans obtained via advanced eco-friendly technologies from marine resources.the present review article is intended to direct attention to the technological advances made in the 2010-2014 quinquennium for the isolation and manufacture of nanofibrillar chitin and chitosan. otherwise called nanocrystals or whiskers, n-chitin and n-chitosan are obtained either by mechanical chitin disassembly and fibrillation optionally assisted by sonication, or by e-spinning of solutions of polysaccharides often accompanied by poly(ethylene oxide) or poly(caprolactone). the biomedical are ...201425415349
mosquito immunity against arboviruses.arthropod-borne viruses (arboviruses) pose a significant threat to global health, causing human disease with increasing geographic range and severity. the recent availability of the genome sequences of medically important mosquito species has kick-started investigations into the molecular basis of how mosquito vectors control arbovirus infection. here, we discuss recent findings concerning the role of the mosquito immune system in antiviral defense, interactions between arboviruses and fundament ...201425415198
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
vaccines against respiratory viral pathogens for use in neonates: opportunities and challenges.the first six months of life reflect a time of high susceptibility to severe disease following respiratory virus infection. although this could be improved significantly by immunization, current vaccines are not approved for use in these very young individuals. this is the result of the combined effects of poor immune responsiveness and safety concerns regarding the use of live attenuated vaccines or potent adjuvants in this population. vaccines to effectively combat respiratory viral infection ...025411431
detection of chikungunya virus antigen by a novel rapid immunochromatographic test.chikungunya fever is a mosquito-borne disease of key public health importance in tropical and subtropical countries. although severe joint pain is the most distinguishing feature of chikungunya fever, diagnosis remains difficult because the symptoms of chikungunya fever are shared by many pathogens, including dengue fever. the present study aimed to develop a new immunochromatographic diagnosis test for the detection of chikungunya virus antigen in serum. mice were immunized with isolates from p ...201425411170
murine herc6 plays a critical role in protein isgylation in vivo and has an isgylation-independent function in seminal vesicles.isg15 conjugation (isgylation) to proteins is a multistep process involving interferon (ifn)-inducible ube1l (e1), ubch8 (e2), and isg15 e3 ligases (e3s). studies performed over the past several years have shown that isgylation plays a pivotal role in the host antiviral response against certain viruses. recent in vitro studies revealed that human herc5 and mouse herc6 are major isg15 e3 ligases, respectively. however, the global function of herc5/6 proteins in vivo still remains unclear. here, w ...201425406959
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
enterovirus 71 induces mitochondrial reactive oxygen species generation that is required for efficient replication.redox homeostasis is an important host factor determining the outcome of infectious disease. enterovirus 71 (ev71) infection has become an important endemic disease in southeast asia and china. we have previously shown that oxidative stress promotes viral replication, and progeny virus induces oxidative stress in host cells. the detailed mechanism for reactive oxygen species (ros) generation in infected cells remains elusive. in the current study, we demonstrate that mitochondria were a major ro ...201425401329
autophagy and checkpoints for intracellular pathogen defense.autophagy plays a crucial role in intracellular defense against various pathogens. xenophagy is a form of selective autophagy that targets intracellular pathogens for degradation. in addition, several related, yet distinct, intracellular defense responses depend on autophagy-related genes. this review gives an overview of these processes, pathogen strategies to subvert them, and their crosstalk with various cell death programs.025394238
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
a drosophila toolkit for the visualization and quantification of viral replication launched from transgenic genomes.arthropod rna viruses pose a serious threat to human health, yet many aspects of their replication cycle remain incompletely understood. here we describe a versatile drosophila toolkit of transgenic, self-replicating genomes ('replicons') from sindbis virus that allow rapid visualization and quantification of viral replication in vivo. we generated replicons expressing luciferase for the quantification of viral replication, serving as useful new tools for large-scale genetic screens for identify ...201425386852
mechanism and treatment for learning and memory deficits in mouse models of noonan syndrome.in noonan syndrome (ns) 30-50% of subjects show cognitive deficits of unknown etiology and with no known treatment. here, we report that knock-in mice expressing either of two ns-associated mutations in ptpn11, which encodes the nonreceptor protein tyrosine phosphatase shp2, show hippocampal-dependent impairments in spatial learning and deficits in hippocampal long-term potentiation (ltp). in addition, viral overexpression of an ns-associated allele ptpn11(d61g) in adult mouse hippocampus result ...201425383899
parp13 regulates cellular mrna post-transcriptionally and functions as a pro-apoptotic factor by destabilizing trailr4 transcript.poly(adp-ribose) polymerase-13 (parp13/zap/zc3hav1) is an antiviral factor, active against specific rna viruses such as murine leukaemia virus, sindbis virus and human immunodeficiency virus. during infection, parp13 binds viral rna via its four ccch-type zinc-finger domains and targets it for degradation by recruiting cellular messenger rna (mrna) decay factors such as the exosome complex and xrn1. here we show that parp13 binds to and regulates cellular mrnas in the absence of viral infection. ...201425382312
targeting axonal protein synthesis in neuroregeneration and degeneration.localized protein synthesis is a mechanism by which morphologically polarized cells react in a spatially confined and temporally acute manner to changes in their environment. during the development of the nervous system intra-axonal protein synthesis is crucial for the establishment of neuronal connections. in contrast, mature axons have long been considered as translationally inactive but upon nerve injury or under neurodegenerative conditions specific subsets of mrnas are recruited into axons ...025371166
interleukin 10 modulation of pathogenic th17 cells during fatal alphavirus encephalomyelitis.mosquito-borne alphaviruses are important causes of epidemic encephalomyelitis. neuronal cell death during fatal alphavirus encephalomyelitis is immune-mediated; however, the types of cells involved and their regulation have not been determined. we show that the virus-induced inflammatory response was accompanied by production of the regulatory cytokine il-10, and in the absence of il-10, paralytic disease occurred earlier and mice died faster. to determine the reason for accelerated disease in ...201425362048
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
a cytoplasmic rna virus generates functional viral small rnas and regulates viral ires activity in mammalian cells.the roles of virus-derived small rnas (vsrnas) have been studied in plants and insects. however, the generation and function of small rnas from cytoplasmic rna viruses in mammalian cells remain unexplored. this study describes four vsrnas that were detected in enterovirus 71-infected cells using next-generation sequencing and northern blots. viral infection produced substantial levels (>10(5) copy numbers per cell) of vsrna1, one of the four vsrnas. we also demonstrated that dicer is involved in ...201425352551
cellular responses to sindbis virus infection of neural progenitors derived from human embryonic stem cells.sindbis virus (sinv) causes age-dependent encephalitis in mice, and therefore serves as a model to study viral encephalitis. sinv is used as a vector for the delivery of genes into selected neural stem cell lines; however, the toxicity and side effects of this vector have rarely been discussed. in this context, we investigated the cellular responses of human embryonic stem cell (hescs) derived neural progenitors (hnpcs) to sinv infection by assessing susceptibility of the cells to sinv infection ...201425343994
arboviral bottlenecks and challenges to maintaining diversity and fitness during mosquito transmission.the term arbovirus denotes viruses that are transmitted by arthropods, such as ticks, mosquitoes, and other biting arthropods. the infection of these vectors produces a certain set of evolutionary pressures on the virus; involving migration from the midgut, where the blood meal containing the virus is processed, to the salivary glands, in order to transmit the virus to the next host. during this process the virus is subject to numerous bottlenecks, stochastic events that significantly reduce the ...201425341663
ribosomal readthrough at a short uga stop codon context triggers dual localization of metabolic enzymes in fungi and animals.translation of mrna into a polypeptide chain is a highly accurate process. many prokaryotic and eukaryotic viruses, however, use leaky termination of translation to optimize their coding capacity. although growing evidence indicates the occurrence of ribosomal readthrough also in higher organisms, a biological function for the resulting extended proteins has been elucidated only in very few cases. here, we report that in human cells programmed stop codon readthrough is used to generate peroxisom ...201425340584
autophagy restricts hiv-1 infection by selectively degrading tat in cd4+ t lymphocytes.autophagy is a ubiquitous mechanism involved in the lysosomal-mediated degradation of cellular components when they are engulfed in vacuoles called autophagosomes. autophagy is also recognized as an important regulator of the innate and adaptive immune responses against numerous pathogens, which have, therefore, developed strategies to block or use the autophagy machinery to their own benefit. upon human immunodeficiency virus type 1 (hiv-1) infection, viral envelope (env) glycoproteins induce a ...201425339774
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
parkin mutations reduce the complexity of neuronal processes in ipsc-derived human neurons.parkinson's disease (pd) is characterized by the degeneration of nigral dopaminergic (da) neurons and non-da neurons in many parts of the brain. mutations of parkin, an e3 ubiquitin ligase that strongly binds to microtubules, are the most frequent cause of recessively inherited pd. the lack of robust pd phenotype in parkin knockout mice suggests a unique vulnerability of human neurons to parkin mutations. here, we show that the complexity of neuronal processes as measured by total neurite length ...025332110
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
inhibition of host protein synthesis by sindbis virus: correlation with viral rna replication and release of nuclear proteins to the cytoplasm.infection of mammalian cells by sindbis virus (sinv) profoundly blocks cellular mrna translation. experimental evidence points to viral non-structural proteins (nsps), in particular nsp2, as the mediator of this inhibition. however, individual expression of nsp1, nsp2, nsp3 or nsp1-4 does not block cellular protein synthesis in bhk cells. trans-complementation of a defective sinv replicon lacking most of the coding region for nsps by the co-expression of nsp1-4 propitiates viral rna replication ...201525329362
the ubiquitin c-terminal hydrolase l1 (uch-l1) c terminus plays a key role in protein stability, but its farnesylation is not required for membrane association in primary neurons.ubiquitin c-terminal hydrolase l1 (uch-l1) is a deubiquitinating enzyme that is highly expressed in neurons. a possible role for uch-l1 in neurodegeneration has been highlighted because of its presence in lewy bodies associated with parkinson disease and neurofibrillary tangles observed in alzheimer disease. uch-l1 exists in two forms in neurons, a soluble cytoplasmic form (uch-l1(c)) and a membrane-associated form (uch-l1(m)). alzheimer brains show reduced levels of soluble uch-l1(c) correlatin ...201425326379
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
novel mode of isg15-mediated protection against influenza a virus and sendai virus in mice.isg15 is a diubiquitin-like modifier and one of the most rapidly induced genes upon type i interferon stimulation. hundreds of host proteins and a number of viral proteins have been shown to be isgylated, and understanding how these modifications affect the interferon response and virus replication has been of considerable interest. isg15(-/-) mice exhibit increased susceptibility to viral infection, and in the case of influenza b virus and vaccinia virus, isg15 conjugation has been shown to res ...201425320315
variations in ph sensitivity, acid stability, and fusogenicity of three influenza virus h3 subtypes.influenza a virus strains adapt to achieve successful entry into host species. entry is mediated by the viral membrane protein hemagglutinin (ha), which triggers membrane fusion and genome release under acidic conditions in the endosome. in addition to changes in the receptor binding domain, the acid stability of ha has been linked to the successful transmission of virus between avian and human hosts. however, to fully understand the connection between changes in ha and host tropism, additional ...201425320308
venezuelan equine encephalitis virus variants lacking transcription inhibitory functions demonstrate highly attenuated phenotype.alphaviruses represent a significant public health threat worldwide. they are transmitted by mosquitoes and cause a variety of human diseases ranging from severe meningoencephalitis to polyarthritis. to date, no efficient and safe vaccines have been developed against any alphavirus infection. however, in recent years, significant progress has been made in understanding the mechanism of alphavirus replication and virus-host interactions. these data have provided the possibility for the developmen ...201425320296
differentiation of neurons restricts arbovirus replication and increases expression of the alpha isoform of irf-7.susceptibility to alphavirus infection is age dependent, and host maturation is associated with decreased virus replication and less severe encephalitis. to identify factors associated with maturation-dependent restriction of virus replication, we studied ap-7 rat olfactory bulb neuronal cells, which can differentiate in vitro. differentiation was associated with a 150- to 1,000-fold decrease in replication of the alphaviruses sindbis virus and venezuelan equine encephalitis virus, as well as la ...201425320290
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
alginate hydrogel protects encapsulated hepatic huh-7 cells against hepatitis c virus and other viral infections.cell microencapsulation in alginate hydrogel has shown interesting applications in regenerative medicine and the biomedical field through implantation of encapsulated tissue or for bioartificial organ development. although alginate solution is known to have low antiviral activity, the same property regarding alginate gel has not yet been studied. the aim of this work is to investigate the potential protective effect of alginate encapsulation against hepatitis c virus (hcv) infection for a hepati ...201425310111
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
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
phosphatidylserine receptors: enhancers of enveloped virus entry and infection.a variety of both rna and dna viruses envelop their capsids in a lipid bilayer. one of the more recently appreciated benefits this envelope is incorporation of phosphatidylserine (ptdser). surface exposure of ptdser disguises viruses as apoptotic bodies; tricking cells into engulfing virions. this mechanism is termed apoptotic mimicry. several ptdser receptors have been identified to enhance virus entry and we have termed this group of proteins ptdser-mediated virus entry enhancing receptors or ...201425277499
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
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
drosophila c virus systemic infection leads to intestinal obstruction.drosophila c virus (dcv) is a positive-sense rna virus belonging to the dicistroviridae family. this natural pathogen of the model organism drosophila melanogaster is commonly used to investigate antiviral host defense in flies, which involves both rna interference and inducible responses. although lethality is used routinely as a readout for the efficiency of the antiviral immune response in these studies, virus-induced pathologies in flies still are poorly understood. here, we characterize the ...201425253354
antiviral activity of lanatoside c against dengue virus infection.dengue infection poses a serious threat globally due to its recent rapid spread and rise in incidence. currently, there is no approved vaccine or effective antiviral drug for dengue virus infection. in response to the urgent need for the development of an effective antiviral for dengue virus, the us drug collection library was screened in this study to identify compounds with anti-dengue activities. lanatoside c, an fda approved cardiac glycoside was identified as a candidate anti-dengue compoun ...201425251726
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
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
potent immune responses in rhesus macaques induced by nonviral delivery of a self-amplifying rna vaccine expressing hiv type 1 envelope with a cationic nanoemulsion.self-amplifying messenger rna (mrna) of positive-strand rna viruses are effective vectors for in situ expression of vaccine antigens and have potential as a new vaccine technology platform well suited for global health applications. the sam vaccine platform is based on a synthetic, self-amplifying mrna delivered by a nonviral delivery system. the safety and immunogenicity of an hiv sam vaccine encoding a clade c envelope glycoprotein formulated with a cationic nanoemulsion (cne) delivery system ...201425234719
development and application of a reversed-phase high-performance liquid chromatographic method for quantitation and characterization of a chikungunya virus-like particle vaccine.to effectively support the development of a chikungunya (chikv) virus-like particle (vlp) vaccine, a sensitive and robust high-performance liquid chromatography (hplc) method that can quantitate chikv vlps and monitor product purity throughout the manufacturing process is needed. we developed a sensitive reversed-phase hplc (rp-hplc) method that separates capsid, e1, and e2 proteins in chikv vlp vaccine with good resolution. each protein component was verified by sodium dodecyl sulfate polyacryl ...201425234500
sponging of cellular proteins by viral rnas.viral rnas accumulate to high levels during infection and interact with a variety of cellular factors including mirnas and rna-binding proteins. although many of these interactions exist to directly modulate replication, translation and decay of viral transcripts, evidence is emerging that abundant viral rnas may in certain cases serve as a sponge to sequester host non-coding rnas and proteins. by effectively reducing the ability of cellular rna binding proteins to regulate host cell gene expres ...201425233339
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
virus-mediated compartmentalization of the host translational machinery.viruses require the host translational apparatus to synthesize viral proteins. host stress response mechanisms that suppress translation, therefore, represent a significant obstacle that viruses must overcome. here, we report a strategy whereby the mammalian orthoreoviruses compartmentalize the translational machinery within virus-induced inclusions known as viral factories (vf). vf are the sites of reovirus replication and assembly but were thought not to contain ribosomes. it was assumed viral ...201425227463
computational identification of dengue virus microrna-like structures and their cellular targets.micrornas (mirnas) are small, noncoding rna molecules that regulate transcriptional and posttranscriptional gene regulation of the cell. experimental evidence shows that mirnas have a direct role in different cellular processes, such as immune function, apoptosis, and tumorigenesis. in a viral infection context, mirnas have been connected with the interplay between host and pathogen, occupying a major role in pathogenesis. while numerous viral mirnas from dna viruses have been identified, charac ...201425210446
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
viruses and rna interference: issues and controversies.the question of whether any mammalian cells are able to mount an effective rna interference-mediated antiviral innate immune response has remained highly controversial. in this gem, i review recent data addressing this important issue and propose a testable hypothesis that can explain many of the apparently contradictory results published in this area of research.201425210170
differential release of β-amyloid from dendrite- versus axon-targeted app.the β-amyloid precursor protein (app) plays a central role in the pathogenesis of alzheimer's disease. app is processed in neurons, but little is known about the relative contributions of presynaptic or postsynaptic compartments to the release of aβ peptides. to address this issue, we transduced primary neurons from sprague-dawley rats or app(-/-) mice (b6.129s7-app(tm1dbo)/j) with lentiviral constructs expressing app chimeras harboring targeting motifs from low-density lipoprotein receptor or n ...025209273
il-1r1 signaling regulates cxcl12-mediated t cell localization and fate within the central nervous system during west nile virus encephalitis.immune cell entry into the virally infected cns is vital for promoting viral clearance yet may contribute to neuropathology if not rigorously regulated. we previously showed that signaling through il-1r1 is critical for effector t cell reactivation and virologic control within the cns during murine west nile virus (wnv) encephalitis. wnv-infected il-1r1(-/-) mice also display increased parenchymal penetration of cd8(+) t cells despite lack of cd4-mediated full activation, suggesting dysregulatio ...201425200953
nup98 promotes antiviral gene expression to restrict rna viral infection in drosophila.in response to infection, the innate immune system rapidly activates an elaborate and tightly orchestrated gene expression program to induce critical antimicrobial genes. while many key players in this program have been identified in disparate biological systems, it is clear that there are additional uncharacterized mechanisms at play. our previous studies revealed that a rapidly-induced antiviral gene expression program is active against disparate human arthropod-borne viruses in drosophila. mo ...201425197089
intracellular sensing of complement c3 activates cell autonomous immunity.pathogens traverse multiple barriers during infection, including cell membranes. we found that during this transition, pathogens carried covalently attached complement c3 into the cell, triggering immediate signaling and effector responses. sensing of c3 in the cytosol activated mitochondrial antiviral signaling (mavs)-dependent signaling cascades and induced proinflammatory cytokine secretion. c3 also flagged viruses for rapid proteasomal degradation, preventing their replication. this system c ...201425190799
viral rnas are unusually compact.a majority of viruses are composed of long single-stranded genomic rna molecules encapsulated by protein shells with diameters of just a few tens of nanometers. we examine the extent to which these viral rnas have evolved to be physically compact molecules to facilitate encapsulation. measurements of equal-length viral, non-viral, coding and non-coding rnas show viral rnas to have among the smallest sizes in solution, i.e., the highest gel-electrophoretic mobilities and the smallest hydrodynamic ...201425188030
picornavirus morphogenesis.the picornaviridae represent a large family of small plus-strand rna viruses that cause a bewildering array of important human and animal diseases. morphogenesis is the least-understood step in the life cycle of these viruses, and this process is difficult to study because encapsidation is tightly coupled to genome translation and rna replication. although the basic steps of assembly have been known for some time, very few details are available about the mechanism and factors that regulate this ...025184560
inhibition of west nile virus by calbindin-d28k.evidence indicates that west nile virus (wnv) employs ca(2+) influx for its replication. moreover, calcium buffer proteins, such as calbindin d28k (cb-d28k), may play an important role mitigating cellular destruction due to disease processes, and more specifically, in some neurological diseases. we addressed the hypothesis that cb-d28k inhibits wnv replication in cell culture and infected rodents. wnv envelope immunoreactivity (ir) was not readily co-localized with cb-d28k ir in wnv-infected ver ...201425180779
fusion-related host proteins are actively regulated by na during influenza infection as revealed by quantitative proteomics analysis.three recombinant influenza a viruses with different neuraminidases (nas) in the background of a/pr/8/34 (pr8), named rpr8-h5n1na, rpr8-h9n2na, and rpr8-h1n1na, derived from h5n1, h9n2, h1n1 (swine) viruses, respectively, were constructed. we performed a quantitative proteomics analysis to investigate differential protein expression in madin-darby canine kidney (mdck) cells infected with recombinant and wild-type influenza viruses to determine whether na replacement would alter host cell gene ex ...201425153908
assembly and maturation of a t = 4 quasi-equivalent virus is guided by electrostatic and mechanical forces.nudaurelia capensis w virus (nωv) is a eukaryotic rna virus that is well suited for the study of virus maturation. the virus initially assembles at ph 7.6 into a marginally stable 480-å procapsid formed by 240 copies of a single type of protein subunit. during maturation, which occurs during apoptosis at ph 5.0, electrostatic forces guide subunit trajectories into a robust 410-å virion that is buttressed by subunit associated molecular switches. we discuss the competing factors in the virus caps ...201425153346
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
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
stem-loop recognition by ddx17 facilitates mirna processing and antiviral defense.dead-box helicases play essential roles in rna metabolism across species, but emerging data suggest that they have additional functions in immunity. through rnai screening, we identify an evolutionarily conserved and interferon-independent role for the dead-box helicase ddx17 in restricting rift valley fever virus (rvfv), a mosquito-transmitted virus in the bunyavirus family that causes severe morbidity and mortality in humans and livestock. loss of drosophila ddx17 (rm62) in cells and flies enh ...025126784
regulation of autophagic activation by rta of epstein-barr virus via the extracellular signal-regulated kinase pathway.autophagy is an intracellular degradation pathway that provides a host defense mechanism against intracellular pathogens. however, many viruses exploit this mechanism to promote their replication. this study shows that lytic induction of epstein-barr virus (ebv) increases the membrane-bound form of lc3 (lc3-ii) and lc3-containing punctate structures in ebv-positive cells. transfecting 293t cells with a plasmid that expresses rta also induces autophagy, revealing that rta is responsible for autop ...201425122800
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
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
development of a reverse genetics system for respiratory syncytial virus long strain and an immunogenicity study of the recombinant virus.respiratory syncytial virus (rsv) is an important human respiratory pathogen, particularly of infants and older adults, and despite several decades of research and development, no licensed vaccine is available. studies have confirmed that enhancement of rsv disease does not occur after inoculation with rsv live-attenuated vaccine candidates, making such vaccines preferable. in this paper, reverse genetics was used to construct two recombinant viruses, a recombinant long strain (rlong) and rlong- ...201425107552
development of an algorithm for production of inactivated arbovirus antigens in cell culture.arboviruses are medically important pathogens that cause human disease ranging from a mild fever to encephalitis. laboratory diagnosis is essential to differentiate arbovirus infections from other pathogens with similar clinical manifestations. the arboviral diseases branch (adb) reference laboratory at the cdc division of vector-borne diseases (dvbd) produces reference antigens used in serological assays such as the virus-specific immunoglobulin m antibody-capture enzyme-linked immunosorbent as ...201425102428
suppressing dengue-2 infection by chemical inhibition of aedes aegypti host factors.dengue virus host factors (denv hfs) that are essential for the completion of the infection cycle in the mosquito vector and vertebrate host represent potent targets for transmission blocking. here we investigated whether known mammalian denv hf inhibitors could influence virus infection in the arthropod vector a. aegypti. we evaluated the potency of bafilomycin (baf; inhibitor of vacuolar h+-atpase (vatpase)), mycophenolic acid (mpa; inhibitor of inosine-5'-monophosphate dehydrogenase (impdh)), ...201425101828
a chimeric virus-mouse model system for evaluating the function and inhibition of papain-like proteases of emerging coronaviruses.to combat emerging coronaviruses, developing safe and efficient platforms to evaluate viral protease activities and the efficacy of protease inhibitors is a high priority. here, we exploit a biosafety level 2 (bsl-2) chimeric sindbis virus system to evaluate protease activities and the efficacy of inhibitors directed against the papain-like protease (plpro) of severe acute respiratory syndrome coronavirus (sars-cov), a biosafety level 3 (bsl-3) pathogen. we engineered sindbis virus to coexpress ...201425100850
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
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
engineering recombinant orsay virus directly in the metazoan host caenorhabditis elegans.the recent identification of orsay virus, the first virus that is capable of naturally infecting caenorhabditis elegans, provides a unique opportunity to explore host-virus interaction studies in this invaluable model organism. a key feature of this system is the robust genetic tractability of the host, c. elegans, which would ideally be complemented by the ability to genetically manipulate orsay virus in parallel. to this end, we developed a plasmid-based reverse genetics system for orsay virus ...201425078701
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
immunization of mice with lentiviral vectors targeted to mhc class ii+ cells is due to preferential transduction of dendritic cells in vivo.gene transfer vectors such as lentiviral vectors offer versatile possibilities to express transgenic antigens for vaccination purposes. however, viral vaccines leading to broad transduction and transgene expression in vivo, are undesirable. therefore, strategies capable of directing gene transfer only to professional antigen-presenting cells would increase the specific activity and safety of genetic vaccines. a lentiviral vector pseudotype specific for murine major histocompatibilty complex clas ...201425058148
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
short self-interacting n-terminal region of rubella virus capsid protein is essential for cooperative actions of capsid and nonstructural p150 proteins.nucleocapsid formation is a primary function of the rubella virus capsid protein, which also promotes viral rna synthesis via an unknown mechanism. the present study demonstrates that in infected cells, the capsid protein is associated with the nonstructural p150 protein via the short self-interacting n-terminal region of the capsid protein. mutational analyses indicated that hydrophobic amino acids in this n-terminal region are essential for its n-terminal self-interaction, which is critical fo ...201425056903
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