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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
more novel hantaviruses and diversifying reservoir hosts--time for development of reservoir-derived cell culture models?due to novel, improved and high-throughput detection methods, there is a plethora of newly identified viruses within the genus hantavirus. furthermore, reservoir host species are increasingly recognized besides representatives of the order rodentia, now including members of the mammalian orders soricomorpha/eulipotyphla and chiroptera. despite the great interest created by emerging zoonotic viruses, there is still a gross lack of in vitro models, which reflect the exclusive host adaptation of mo ...201424576845
critical role of interferon-α constitutively produced in human hepatocytes in response to rna virus infection.several viruses are known to infect human liver and cause the hepatitis, but the interferon (ifn) response, a first-line defense against viral infection, of virus-infected hepatocytes is not clearly defined yet. we investigated innate immune system against rna viral infection in immortalized human hepatocytes (hus-e/2 cells), as the cells showed similar early innate immune responses to primary human hepatocytes (phh). the low-level constitutive expression of ifn-α1 gene, but not ifn-β and ifn-λ, ...201424587086
dynamic survey of mitochondria by ubiquitin.ubiquitin is a post-translational modifier with proteolytic and non-proteolytic roles in many biological processes. at mitochondria, it performs regulatory homeostatic functions and contributes to mitochondrial quality control. ubiquitin is essential for mitochondrial fusion, regulates mitochondria-er contacts, and participates in maternal mtdna inheritance. under stress, mitochondrial dysfunction induces ubiquitin-dependent responses that involve mitochondrial proteome remodeling and culminate ...201424569520
the yellow fever 17d virus as a platform for new live attenuated vaccines.the live-attenuated yellow fever 17d virus is one of the most outstanding human vaccines ever developed. it induces efficacious immune responses at a low production cost with a well-established manufacture process. these advantages make the yf17d virus attractive as a vector for the development of new vaccines. at the beginning of vector development studies, yf17d was genetically manipulated to express other flavivirus prm and e proteins, components of the viral envelope. while these 17d recombi ...201424553128
the role of ikkβ in venezuelan equine encephalitis virus infection.venezuelan equine encephalitis virus (veev) belongs to the genus alphavirus, family togaviridae. veev infection is characterized by extensive inflammation and studies from other laboratories implicated an involvement of the nf-κb cascade in the in vivo pathology. initial studies indicated that at early time points of veev infection, the nf-κb complex was activated in cells infected with the tc-83 strain of veev. one upstream kinase that contributes to the phosphorylation of p65 is the ikkβ compo ...201424586253
genome-wide rnai screen identifies broadly-acting host factors that inhibit arbovirus infection.vector-borne viruses are an important class of emerging and re-emerging pathogens; thus, an improved understanding of the cellular factors that modulate infection in their respective vertebrate and insect hosts may aid control efforts. in particular, cell-intrinsic antiviral pathways restrict vector-borne viruses including the type i interferon response in vertebrates and the rna interference (rnai) pathway in insects. however, it is likely that additional cell-intrinsic mechanisms exist to limi ...201424550726
interferon-stimulated genes: a complex web of host defenses.interferon-stimulated gene (isg) products take on a number of diverse roles. collectively, they are highly effective at resisting and controlling pathogens. in this review, we begin by introducing interferon (ifn) and the jak-stat signaling pathway to highlight features that impact isg production. next, we describe ways in which isgs both enhance innate pathogen-sensing capabilities and negatively regulate signaling through the jak-stat pathway. several isgs that directly inhibit virus infection ...201424555472
a gammaherpesvirus bcl-2 ortholog blocks b cell receptor-mediated apoptosis and promotes the survival of developing b cells in vivo.gammaherpesviruses such as epstein-barr virus (ebv) and kaposi's sarcoma-associated herpesvirus (kshv, hhv-8) establish lifelong latency in their hosts and are associated with the development of several types of malignancies, including a subset of b cell lymphomas. these viruses are thought to co-opt the process of b cell differentiation to latently infect a fraction of circulating memory b cells, resulting in the establishment of a stable latency setpoint. however, little is known about how thi ...201424516386
microrna-like viral small rna from dengue virus 2 autoregulates its replication in mosquito cells.micrornas (mirnas) are small regulatory rnas that play significant roles in most cellular processes. in the seemingly endless arms race between hosts and pathogens, viruses also encode mirnas that facilitate successful infection. in search of functional mirnas or viral small rnas (vsrnas) encoded by dengue virus (denv), deep sequencing data of virus-infected aedes aegypti mosquitoes were used. from six vsrnas, with candidate stem-loop structures in the 5' and 3' untranslated regions of the viral ...201424550303
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
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
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
isg15 functions as an interferon-mediated antiviral effector early in the murine norovirus life cycle.human noroviruses (hunov) are the leading cause of nonbacterial gastroenteritis worldwide. similar to hunov, murine noroviruses (mnv) are enteric pathogens spread via the fecal-oral route and have been isolated from numerous mouse facilities worldwide. type i and type ii interferons (ifn) restrict mnv-1 replication; however, the antiviral effectors impacting mnv-1 downstream of ifn signaling are largely unknown. studies using dendritic cells, macrophages, and mice deficient in free and conjugate ...201424899198
western equine encephalitis virus: evolutionary analysis of a declining alphavirus based on complete genome sequences.western equine encephalitis virus (weev) is an arbovirus from the genus alphavirus, family togaviridae, which circulates in north america between birds and mosquitoes, occasionally causing disease in humans and equids. in recent decades, human infection has decreased dramatically; the last documented human case in north america occurred in 1994, and the virus has not been detected in mosquito pools since 2008. because limited information exists regarding the evolution of weev, we analyzed the ge ...201424899192
defective viral genomes: critical danger signals of viral infections.viruses efficiently block the host antiviral response in order to replicate and spread before host intervention. the mechanism initiating antiviral immunity during stealth viral replication is unknown, but recent data demonstrate that defective viral genomes generated at peak virus replication are critical for this process in vivo. this article summarizes the supporting evidence and highlights gaps in our understanding of the mechanisms and impact of immunostimulatory defective viral genomes gen ...201424872580
progression from igd+ igm+ to isotype-switched b cells is site specific during coronavirus-induced encephalomyelitis.various infections in the central nervous system (cns) trigger b cell accumulation; however, the relative dynamics between viral replication and alterations in distinct b cell subsets are largely unknown. using a glia-tropic coronavirus infection, which is initiated in the brain but rapidly spreads to and predominantly persists in the spinal cord, this study characterizes longitudinal changes in b cell subsets at both infected anatomical sites. the phase of t cell-dependent, antibody-independent ...201424872583
nonneutralizing functional antibodies: a new "old" paradigm for hiv vaccines.animal and human data from various viral infections and vaccine studies suggest that nonneutralizing antibodies (nnab) without neutralizing activity in vitro may play an important role in protection against viral infection in vivo. this was illustrated by the recent human immunodeficiency virus (hiv) rv144 vaccine efficacy trial, which demonstrated that hiv-specific igg-mediated nnab directed against the v2 loop of hiv type 1 envelope (env) were inversely correlated with risk for hiv acquisition ...201424920599
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
population structure and distribution patterns of the sibling mosquito species culex pipiens and culex torrentium (diptera: culicidae) reveal different evolutionary paths.nowadays a number of endemic mosquito species are known to possess vector abilities for various diseases, as e.g. the sibling species culex pipiens and culex torrentium. due to their morphological similarity, ecology, distribution and vector abilities, knowledge about these species' population structure is essential. culicidae from 25 different sampling sites were collected from march till october 2012. all analyses were performed with aligned cox1 sequences with a total length of 658 bp. popula ...201425048456
novel drosophila viruses encode host-specific suppressors of rnai.the ongoing conflict between viruses and their hosts can drive the co-evolution between host immune genes and viral suppressors of immunity. it has been suggested that an evolutionary 'arms race' may occur between rapidly evolving components of the antiviral rnai pathway of drosophila and viral genes that antagonize it. we have recently shown that viral protein 1 (vp1) of drosophila melanogaster nora virus (dmelnv) suppresses argonaute-2 (ago2)-mediated target rna cleavage (slicer activity) to a ...201425032815
japanese encephalitis virus replication is negatively regulated by autophagy and occurs on lc3-i- and edem1-containing membranes.autophagy is a lysosomal degradative pathway that has diverse physiological functions and plays crucial roles in several viral infections. here we examine the role of autophagy in the life cycle of jev, a neurotropic flavivirus. jev infection leads to induction of autophagy in several cell types. jev replication was significantly enhanced in neuronal cells where autophagy was rendered dysfunctional by atg7 depletion, and in atg5-deficient mouse embryonic fibroblasts (mefs), resulting in higher v ...201425046112
the impact of the interferon-lambda family on the innate and adaptive immune response to viral infections.type-iii interferons (ifn-λ, ifnl) are the most recently described family of ifns. this family of innate cytokines are increasingly being ascribed pivotal roles in host-pathogen interactions. herein, we will review the accumulating evidence detailing the immune biology of ifnl during viral infection, and the implications of this novel information on means to advance the development of therapies and vaccines against existing and emerging pathogens. ifnls exert antiviral effects via induction of i ...201426038748
ebv microrna bart 18-5p targets map3k2 to facilitate persistence in vivo by inhibiting viral replication in b cells.ebv is an oncogenic human herpesvirus that has the ability to infect and transform b cells latently in vitro. however, the virus also establishes a lifetime, benign, persistent latent infection in resting memory b cells in vivo, where the virus is quiescent (i.e., expresses none of the known latent proteins). the virus encodes ∼40 micro-rnas (mirnas), most of which are transcribed from the bamh1 fragment a rightward transcript (bart) region of the virus. we have shown previously that a subset of ...201425012295
cdk9 inhibitor fit-039 prevents replication of multiple dna viruses.a wide range of antiviral drugs is currently available; however, drug-resistant viruses have begun to emerge and represent a potential public health risk. here, we explored the use of compounds that inhibit or interfere with the action of essential host factors to prevent virus replication. in particular, we focused on the cyclin-dependent kinase 9 (cdk9) inhibitor, fit-039, which suppressed replication of a broad spectrum of dna viruses through inhibition of mrna transcription. specifically, fi ...201425003190
enhancement of protein expression by alphavirus replicons by designing self-replicating subgenomic rnas.since the development of infectious cdna clones of viral rna genomes and the means of delivery of the in vitro-synthesized rna into cells, alphaviruses have become an attractive system for expression of heterologous genetic information. alphaviruses replicate exclusively in the cytoplasm, and their genetic material cannot recombine with cellular dna. alphavirus genome-based, self-replicating rnas (replicons) are widely used vectors for expression of heterologous proteins. their current design re ...201425002490
association of climatic factors with infectious diseases in the arctic and subarctic region--a systematic review.the arctic and subarctic area are likely to be highly affected by climate change, with possible impacts on human health due to effects on food security and infectious diseases.201424990685
differential restriction patterns of mrna decay factor auf1 during picornavirus infections.during infection by picornaviruses, the cellular environment is modified to favour virus replication. this includes the modification of specific host proteins, including the recently discovered viral proteinase cleavage of mrna decay factor au-rich binding factor 1 (auf1). this cellular rna-binding protein was shown previously to act as a restriction factor during poliovirus, rhinovirus and coxsackievirus infection. during infection by these viruses, auf1 relocalizes to the cytoplasm and is clea ...201424722678
a single vertebrate dna virus protein disarms invertebrate immunity to rna virus infection.virus-host interactions drive a remarkable diversity of immune responses and countermeasures. we found that two rna viruses with broad host ranges, vesicular stomatitis virus (vsv) and sindbis virus (sinv), are completely restricted in their replication after entry into lepidopteran cells. this restriction is overcome when cells are co-infected with vaccinia virus (vacv), a vertebrate dna virus. using rnai screening, we show that lepidopteran rnai, nuclear factor-κb, and ubiquitin-proteasome pat ...201424966209
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
the mammalian response to virus infection is independent of small rna silencing.a successful cellular response to virus infection is essential for evolutionary survival. in plants, arthropods, and nematodes, cellular antiviral defenses rely on rnai. interestingly, the mammalian response to virus is predominantly orchestrated through interferon (ifn)-mediated induction of antiviral proteins. despite the potency of the ifn system, it remains unclear whether mammals also have the capacity to employ antiviral rnai. here, we investigated this by disabling ifn function, small rna ...201424953656
imaging intraorganellar ca2+ at subcellular resolution using cepia.the endoplasmic reticulum (er) and mitochondria accumulate ca(2+) within their lumens to regulate numerous cell functions. however, determining the dynamics of intraorganellar ca(2+) has proven to be difficult. here we describe a family of genetically encoded ca(2+) indicators, named calcium-measuring organelle-entrapped protein indicators (cepia), which can be utilized for intraorganellar ca(2+) imaging. cepia, which emit green, red or blue/green fluorescence, are engineered to bind ca(2+) at i ...201424923787
rift valley fever virus encephalitis is associated with an ineffective systemic immune response and activated t cell infiltration into the cns in an immunocompetent mouse model.rift valley fever virus (rvfv) causes outbreaks of severe disease in livestock and humans throughout africa and the arabian peninsula. in people, rvfv generally causes a self-limiting febrile illness but in a subset of individuals, it progresses to more serious disease. one manifestation is a delayed-onset encephalitis that can be fatal or leave the afflicted with long-term neurologic sequelae. in order to design targeted interventions, the basic pathogenesis of rvfv encephalitis must be better ...201424922480
chemotherapy and oncolytic virotherapy: advanced tactics in the war against cancer.cancer is a traitorous archenemy that threatens our survival. its ability to evade detection and adapt to various cancer therapies means that it is a moving target that becomes increasingly difficult to attack. through technological advancements, we have developed sophisticated weapons to fight off tumor growth and invasion. however, if we are to stand a chance in this war against cancer, advanced tactics will be required to maximize the use of our available resources. oncolytic viruses (ovs) ar ...201424967214
the salivary secretome of the biting midge, culicoides sonorensis.culicoides biting midges (diptera: ceratopogonidae) are hematophagous insects with over 1400 species distributed throughout the world. many of these species are of particular agricultural importance as primary vectors of bluetongue and schmallenberg viruses, yet little is known about culicoides genomics and proteomics. detailed studies of members from other blood-feeding dipteran families, including those of mosquito (culicidae) and black fly (simuliidae), have shown that protein components with ...201424949243
endothelial cell permeability and adherens junction disruption induced by junín virus infection.junín virus (junv) is endemic to the fertile pampas of argentina, maintained in nature by the rodent host calomys musculinus, and the causative agent of argentine hemorrhagic fever (ahf), which is characterized by vascular dysfunction and fluid distribution abnormalities. clinical as well as experimental studies implicate involvement of the endothelium in the pathogenesis of ahf, although little is known of its role. junv has been shown to result in productive infection of endothelial cells (ecs ...201424710609
characterization of metastasis formation and virotherapy in the human c33a cervical cancer model.more than 90% of cancer mortalities are due to cancer that has metastasized. therefore, it is crucial to intensify research on metastasis formation and therapy. here, we describe for the first time the metastasizing ability of the human cervical cancer cell line c33a in athymic nude mice after subcutaneous implantation of tumor cells. in this model, we demonstrated a steady progression of lumbar and renal lymph node metastases during tumor development. besides predominantly occurring lymphatic m ...201424887184
protein interferon-stimulated gene 15 conjugation delays but does not overcome coronavirus proliferation in a model of fulminant hepatitis.coronaviruses express a deubiquitinating protein, the papain-like protease-2 (plp2), that removes both ubiquitin and the ubiquitin-like interferon (ifn)-stimulated gene 15 (isg15) protein from target proteins. isg15 has antiviral activity against a number of viruses; therefore, we examined the effect of isg15 conjugation (isgylation) in a model of acute viral hepatitis induced by the murine hepatitis virus strain 3 (mhv-3) coronavirus. mice deficient in the isg15 deconjugating enzyme, ubiquitin- ...201424648452
identification of ap80978, a novel small-molecule inhibitor of hepatitis c virus replication that targets ns4b.a small-molecule inhibitor of hepatitis c virus (hcv) designated ap89652 was identified by screening a compound library with an hcv genotype 1b subgenomic replicon assay. ap89652 contains two chiral centers, and testing of two syn enantiomers revealed that activity in the replicon assay resided with only one, ap80978, whose 50% effective concentration (ec50) (the concentration at which a 50% reduction in renilla luciferase levels was observed relative to an untreated control) was 630 nm. ap80978 ...201424709254
live attenuated tetravalent dengue virus host range vaccine is immunogenic in african green monkeys following a single vaccination.the causative agent of dengue fever, dengue virus (denv), is transmitted by mosquitoes, and as distribution of these insects has expanded, so has dengue-related disease. denv is a member of the flaviviridae family and has 4 distinct serotypes (denv-1, -2, -3, and -4). no lasting cross protection is afforded to heterologous serotypes following infection by any one of the individual serotypes. the presence of nonneutralizing antibodies to one serotype can facilitate the occurrence of more-severe d ...201424696467
the stress granule component tia-1 binds tick-borne encephalitis virus rna and is recruited to perinuclear sites of viral replication to inhibit viral translation.flaviviruses are a major cause of disease in humans and animals worldwide. tick-borne encephalitis virus (tbev) is the most important arthropod-borne flavivirus endemic in europe and is the etiological agent of tick-borne encephalitis, a potentially fatal infection of the central nervous system. however, the contributions of host proteins during tbev infection are poorly understood. in this work, we investigate the cellular protein tia-1 and its cognate factor tiar, which are stress-induced rna- ...201424696465
imaging the alphavirus exit pathway.alphaviruses are small enveloped rna viruses with highly organized structures that exclude host cell proteins. they contain an internal nucleocapsid and an external lattice of the viral e2 and e1 transmembrane proteins. alphaviruses bud from the plasma membrane (pm), but the process and dynamics of alphavirus assembly and budding are poorly understood. here we generated sindbis viruses (sinvs) with fluorescent protein labels on the e2 envelope protein and exploited them to characterize virus ass ...201424696489
consequences of in vitro host shift for st. louis encephalitis virus.understanding the potential for host range shifts and expansions of rna viruses is critical to predicting the evolutionary and epidemiological paths of these pathogens. as arthropod-borne viruses (arboviruses) experience frequent spillover from their amplification cycles and are generalists by nature, they are likely to experience a relatively high frequency of success in a range of host environments. despite this, the potential for host expansion, the genetic correlates of adaptation to novel e ...201424643879
rapid evolution of parp genes suggests a broad role for adp-ribosylation in host-virus conflicts.post-translational protein modifications such as phosphorylation and ubiquitinylation are common molecular targets of conflict between viruses and their hosts. however, the role of other post-translational modifications, such as adp-ribosylation, in host-virus interactions is less well characterized. adp-ribosylation is carried out by proteins encoded by the parp (also called artd) gene family. the majority of the 17 human parp genes are poorly characterized. however, one parp protein, parp13/za ...201424875882
ontogeny of early life immunity.the human immune system comprises cellular and molecular components designed to coordinately prevent infection while avoiding potentially harmful inflammation and autoimmunity. immunity varies with age, reflecting unique age-dependent challenges including fetal gestation, the neonatal phase, and infancy. here, we review novel mechanistic insights into early life immunity, with an emphasis on emerging models of human immune ontogeny, which may inform age-specific translational development of nove ...201424880460
positron emission tomography image-guided drug delivery: current status and future perspectives.positron emission tomography (pet) is an important modality in the field of molecular imaging, which is gradually impacting patient care by providing safe, fast, and reliable techniques that help to alter the course of patient care by revealing invasive, de facto procedures to be unnecessary or rendering them obsolete. also, pet provides a key connection between the molecular mechanisms involved in the pathophysiology of disease and the according targeted therapies. recently, pet imaging is also ...201424865108
molecular systems pharmacology: isoelectric focusing signature of protein kinase cδ provides an integrated measure of its modulation in response to ligands.protein kinase c (pkc), a validated therapeutic target for cancer chemotherapy, provides a paradigm for assessing structure-activity relations, where ligand binding has multiple consequences for a target. for pkc, ligand binding controls not only pkc activation and multiple phosphorylations but also subcellular localization, affecting subsequent signaling. using a capillary isoelectric focusing immunoassay system, we could visualize a high resolution isoelectric focusing signature of pkcδ upon s ...201424906106
an enu-induced splicing mutation reveals a role for unc93b1 in early immune cell activation following influenza a h1n1 infection.genetic and immunological analysis of host-pathogen interactions can reveal fundamental mechanisms of susceptibility and resistance to infection. modeling human infectious diseases among inbred mouse strains is a proven approach but is limited by naturally occurring genetic diversity. using n-ethyl-n-nitrosourea mutagenesis, we created a recessive loss-of-function point mutation in unc93b1 (unc-93 homolog b1 (c. elegans)), a chaperone for endosomal toll-like receptors (tlr)3, tlr7 and tlr9, whic ...201424848930
local and commissural ic neurons make axosomatic inputs on large gabaergic tectothalamic neurons.large gabaergic (lg) neurons are a distinct type of neuron in the inferior colliculus (ic) identified by their dense vesicular glutamate transporter 2 (vglut2)-containing axosomatic synaptic terminals. yet the sources of these terminals are unknown. since ic glutamatergic neurons express vglut2, and ic neurons are known to have local collaterals, we tested the hypothesis that these excitatory, glutamatergic axosomatic inputs on lg neurons come from local axonal collaterals and commissural ic neu ...201424796971
mechanism for neutralizing activity by the anti-cmv gh/gl monoclonal antibody msl-109.cytomegalovirus (cmv) is a widespread opportunistic pathogen that causes birth defects when transmitted transplacentally and severe systemic illness in immunocompromised individuals. msl-109, a human monoclonal igg isolated from a cmv seropositive individual, binds to the essential cmv entry glycoprotein h (gh) and prevents infection of cells. here, we suggest a mechanism for neutralization activity by msl-109. we define a genetic basis for resistance to msl-109 and have generated a structural m ...201424843144
autophagy in drosophila: from historical studies to current knowledge.the discovery of evolutionarily conserved atg genes required for autophagy in yeast truly revolutionized this research field and made it possible to carry out functional studies on model organisms. insects including drosophila are classical and still popular models to study autophagy, starting from the 1960s. this review aims to summarize past achievements and our current knowledge about the role and regulation of autophagy in drosophila, with an outlook to yeast and mammals. the basic mechanism ...201424949430
ifit1: a dual sensor and effector molecule that detects non-2'-o methylated viral rna and inhibits its translation.our understanding of the antiviral actions of ifit1, one of the most strongly induced interferon stimulated genes (isgs), has advanced remarkably within the last few years. this review focuses on the recent cellular, biochemical, and structural discoveries that have provided new insight as to how ifit1 functions as both a sensor and effector molecule of the cellular innate immune system. ifit1 can detect viral rna lacking 2'-o methylation on their cap structures or displaying a 5'-triphosphate m ...201424909568
a new paradigm: innate immune sensing of viruses via the unfolded protein response.the immune system depends upon combinations of signals to mount appropriate responses: pathogen specific signals in the context of co-stimulatory "danger" signals drive immune strength and accuracy. viral infections trigger anti-viral type i interferon (ifn) responses by stimulating endosomal and cytosolic pattern recognition receptors (prrs). however, viruses have also evolved many strategies to counteract ifn responses. are there intracellular danger signals that enhance immune responses to vi ...201424904537
trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (ampa) receptor subunit glua2 from the endoplasmic reticulum is stimulated by a complex containing ca2+/calmodulin-activated kinase ii (camkii) and pick1 protein and by release of ca2+ from internal stores.the glua2 subunit of the ampa receptor (ampar) dominantly blocks ampar ca(2+) permeability, and its trafficking to the synapse regulates ampar-dependent synapse ca(2+) permeability. here we show that glua2 trafficking from the endoplasmic reticulum (er) to the plasma membrane of cultured hippocampal neurons requires ca(2+) release from internal stores, the activity of ca(2+)/calmodulin activated kinase ii (camkii), and glua2 interaction with the pdz protein, pick1. we show that upon ca(2+) relea ...201424831007
recent progress on c-4-modified podophyllotoxin analogs as potent antitumor agents.podophyllotoxin (ppt), as well as its congeners and derivatives, exhibits pronounced biological activities, especially antineoplastic effects. its strong inhibitory effect on tumor cell growth led to the development of three of the most highly prescribed anticancer drugs in the world, etoposide, teniposide, and the water-soluble prodrug etoposide phosphate. their clinical success as well as intriguing mechanism of action stimulated great interest in further modification of ppt for better antitum ...201424827545
regulation of gap junction channels by infectious agents and inflammation in the cns.gap junctions (gjs) are conglomerates of intercellular channels that connect the cytoplasm of two or more cells, and facilitate the transfer of ions and small molecules, including second messengers, resulting in metabolic and electrical coordination. in general, loss of gap junctional communication (gjc) has been associated with cellular damage and inflammation resulting in compromise of physiological functions. recently, it has become evident that gj channels also play a critical role in the pa ...201424847208
versatile microrna biogenesis in animals and their viruses.micrornas (mirnas) are ubiquitous gene regulators that modulate essential cellular processes at the post-transcriptional level. in metazoans and their viruses, most mirnas are produced from hairpin-containing primary transcripts that are sequentially cleaved by nuclear drosha and cytoplasmic dicer. in the last decade, alternative mechanisms that bypass either the drosha or dicer cleavage step have emerged, increasing the complexity of the mirna regulatory network. here, we highlight non-canonica ...201424823351
complete morphologies of basal forebrain cholinergic neurons in the mouse.the basal forebrain cholinergic system modulates neuronal excitability and vascular tone throughout the cerebral cortex and hippocampus. this system is severely affected in alzheimer's disease (ad), and drug treatment to enhance cholinergic signaling is widely used as symptomatic therapy in ad. defining the full morphologies of individual basal forebrain cholinergic neurons has, until now, been technically beyond reach due to their large axon arbor sizes. using genetically-directed sparse labeli ...201424894464
maraba mg1 virus enhances natural killer cell function via conventional dendritic cells to reduce postoperative metastatic disease.this study characterizes the ability of novel oncolytic rhabdoviruses (maraba mg1) to boost natural killer (nk) cell activity. our results demonstrate that mg1 activates nk cells via direct infection and maturation of conventional dendritic cells. using nk depletion and conventional dendritic cells ablation studies in vivo, we established that both are required for mg1 efficacy. we further explored the efficacy of attenuated mg1 (nonreplicating mg1-uv(2min) and single-cycle replicating mg1-gless ...201424695102
fast gene transfer into the adult zebrafish brain by herpes simplex virus 1 (hsv-1) and electroporation: methods and optogenetic applications.the zebrafish has various advantages as a model organism to analyze the structure and function of neural circuits but efficient viruses or other tools for fast gene transfer are lacking. we show that transgenes can be introduced directly into the adult zebrafish brain by herpes simplex type i viruses (hsv-1) or electroporation. we developed a new procedure to target electroporation to defined brain areas and identified promoters that produced strong long-term expression. the fast workflow of ele ...201424834028
inhibition of dengue virus replication by a class of small-molecule compounds that antagonize dopamine receptor d4 and downstream mitogen-activated protein kinase signaling.dengue viruses (denv) are endemic pathogens of tropical and subtropical regions that cause significant morbidity and mortality worldwide. to date, no vaccines or antiviral therapeutics have been approved for combating denv-associated disease. in this paper, we describe a class of tricyclic small-molecule compounds-dihydrodibenzothiepines (dhbts), identified through high-throughput screening-with potent inhibitory activity against denv serotype 2. ski-417616, a highly active representative of thi ...201424599995
autonomous parvoviruses neither stimulate nor are inhibited by the type i interferon response in human normal or cancer cells.members of the genus parvovirus are small, nonenveloped single-stranded dna viruses that are nonpathogenic in humans but have potential utility as cancer therapeutics. because the innate immune response to parvoviruses has received relatively little attention, we compared the response to parvoviruses to that of several other types of viruses in human cells. in normal human glia, fibroblasts, or melanocytes, vesicular stomatitis virus evoked robust beta interferon (ifn-β) responses. cytomegalovir ...201424554651
drosha as an interferon-independent antiviral factor.utilization of antiviral small interfering rnas is thought to be largely restricted to plants, nematodes, and arthropods. in an effort to determine whether a physiological interplay exists between the host small rna machinery and the cellular response to virus infection in mammals, we evaluated antiviral activity in the presence and absence of dicer or drosha, the rnase iii nucleases responsible for generating small rnas. although loss of dicer did not compromise the cellular response to virus i ...201424778219
single-step antibody-based affinity cryo-electron microscopy for imaging and structural analysis of macromolecular assemblies.single particle cryo-electron microscopy (cryo-em) is an emerging powerful tool for structural studies of macromolecular assemblies (i.e., protein complexes and viruses). although single particle cryo-em requires less concentrated and smaller amounts of samples than x-ray crystallography, it remains challenging to study specimens that are low-abundance, low-yield, or short-lived. the recent development of affinity grid techniques can potentially further extend single particle cryo-em to these ch ...201424780590
proteomics based identification of cell migration related proteins in hbv expressing hepg2 cells.proteomics study was performed to investigate the specific protein expression profiles of hepg2 cells transfected with mutant hbv compared with wildtype hbv genome, aiming to identify the specific functions of sh3 binding domain (proline rich region) located in hbx. in addition to the cell movement and kinetics changes due to the expression of hbv genome we have observed previously, here we further targeted to explore the specific changes of cellular proteins and potential intracellular protein ...201424763314
dicer-2-dependent activation of culex vago occurs via the traf-rel2 signaling pathway.despite their importance as vectors of human and livestock diseases, relatively little is known about innate antiviral immune pathways in mosquitoes and other insects. previous work has shown that culex vago (cxvago), which is induced and secreted from west nile virus (wnv)-infected mosquito cells, acts as a functional homolog of interferon, by activating jak-stat pathway and limiting virus replication in neighbouring cells. here we describe the dicer-2-dependent pathway leading to wnv-induced c ...201424762775
specific retrograde transduction of spinal motor neurons using lentiviral vectors targeted to presynaptic nmj receptors.to understand how receptors are involved in neuronal trafficking and to be able to utilize them for specific targeting via the peripheral route would be of great benefit. here, we describe the generation of novel lentiviral vectors with tropism to motor neurons that were made by coexpressing onto the lentiviral surface a fusogenic glycoprotein (mutated sindbis g) and an antibody against a cell-surface receptor (thy1.1, p75(ntr), or coxsackievirus and adenovirus receptor) on the presynaptic termi ...201424670531
an anterograde rabies virus vector for high-resolution large-scale reconstruction of 3d neuron morphology.glycoprotein-deleted rabies virus (rabv ∆g) is a powerful tool for the analysis of neural circuits. here, we demonstrate the utility of an anterograde rabv ∆g variant for novel neuroanatomical approaches involving either bulk or sparse neuronal populations. this technology exploits the unique features of rabv ∆g vectors, namely autonomous, rapid high-level expression of transgenes, and limited cytotoxicity. our vector permits the unambiguous long-range and fine-scale tracing of the entire axonal ...201424723034
chemical derivatives of a small molecule deubiquitinase inhibitor have antiviral activity against several rna viruses.most antiviral treatment options target the invading pathogen and unavoidably encounter loss of efficacy as the pathogen mutates to overcome replication restrictions. a good strategy for circumventing drug resistance, or for pathogens without treatment options, is to target host cell proteins that are utilized by viruses during infection. the small molecule wp1130 is a selective deubiquitinase inhibitor shown previously to successfully reduce replication of noroviruses and some other rna viruses ...201424722666
complement-related proteins control the flavivirus infection of aedes aegypti by inducing antimicrobial peptides.the complement system functions during the early phase of infection and directly mediates pathogen elimination. the recent identification of complement-like factors in arthropods indicates that this system shares common ancestry in vertebrates and invertebrates as an immune defense mechanism. thioester (te)-containing proteins (teps), which show high similarity to mammalian complement c3, are thought to play a key role in innate immunity in arthropods. herein, we report that a viral recognition ...201424722701
autophagy in macrophages: impacting inflammation and bacterial infection.macrophages are on the front line of host defense. they possess an array of germline-encoded pattern recognition receptors/sensors (prrs) that recognize pathogen-associated molecular patterns (pamps) and which activate downstream effectors/pathways to help mediate innate immune responses and host defense. innate immune responses include the rapid induction of transcriptional networks that trigger the production of cytokines, chemokines, and cytotoxic molecules; the mobilization of cells includin ...201424818040
studies on antimicrobial and immunomodulatory effects of hot aqueous extract of acacia nilotica l. leaves against common veterinary pathogens.acacia nilotica is a plant species that is almost ubiquitously found in different parts of the world. various preparations of it have been advocated in folk medicine for the treatment of tuberculosis, leprosy, smallpox, dysentery, cough, ophthalmia, toothache, skin cancer as astringent, antispasmodic, and aphrodisiac since immemorial times. the present study investigates the antibacterial, antifungal, antiviral, and immunomodulatory potential of hot aqueous extract (hae) of acacia nilotica leave ...201424804150
dynamics of the emergence and establishment of a newly dominant genotype of japanese encephalitis virus throughout asia.in recent years, genotype i (gi) of japanese encephalitis virus (jev) has displaced genotype iii (giii) as the dominant virus genotype throughout asia. in this study, the largest collection of giii and gi envelope gene-derived viral sequences assembled to date was used to reconstruct the spatiotemporal chronology of genotype displacement throughout asia and to determine the evolutionary and epidemiological dynamics underlying this significant event. gi consists of two clades, gi-a and gi-b, with ...201424501419
roles of the putative integrin-binding motif of the human metapneumovirus fusion (f) protein in cell-cell fusion, viral infectivity, and pathogenesis.human metapneumovirus (hmpv) is a relatively recently identified paramyxovirus that causes acute upper and lower respiratory tract infection. entry of hmpv is unusual among the paramyxoviruses, in that fusion is accomplished by the fusion (f) protein without the attachment glycoprotein (g protein). it has been suggested that hmpv f protein utilizes integrin αvβ1 as a cellular receptor. consistent with this, the f proteins of all known hmpv strains possess an integrin-binding motif ((329)rgd(331) ...201424478423
inefficient type i interferon-mediated antiviral protection of primary mouse neurons is associated with the lack of apolipoprotein l9 expression.we examined the antiviral response promoted by type i interferons (ifn) in primary mouse neurons. ifn treatment of neuron cultures strongly upregulated the transcription of ifn-stimulated genes but conferred a surprisingly low resistance to infection by neurotropic viruses such as theiler's murine encephalomyelitis virus (tmev) or vesicular stomatitis virus (vsv). response of primary mouse neurons to ifn treatment was heterogeneous, as many neurons failed to express the typical ifn response mark ...201424453359
prevention of contamination by xenotropic murine leukemia virus-related virus: susceptibility to alcohol-based disinfectants and environmental stability.xenotropic murine leukemia virus-related virus (xmrv) represents a novel γ-retrovirus that is capable of infecting human cells and has been classified as a biosafety level 2 (bsl-2) organism. hence, xmrv represents a potential risk for personnel in laboratories worldwide. here, we measured the stability of xmrv and its susceptibility to alcohol-based disinfectants. to this end, we exposed an infectious xmrv reporter virus encoding a secretable luciferase to different temperatures, ph values, and ...201424532072
the combined use of alphavirus replicons and pseudoinfectious particles for the discovery of antivirals derived from natural products.alphaviruses are a prominent class of reemergent pathogens due to their globally expanding ranges, potential for lethality, and possible use as bioweapons. the absence of effective treatments for alphaviruses highlights the need for innovative strategies to identify antiviral agents. primary screens that use noninfectious self-replicating rnas, termed replicons, have been used to identify potential antiviral compounds for alphaviruses. only inhibitors of viral genome replication, however, will b ...201425550354
antiviral immunity of anopheles gambiae is highly compartmentalized, with distinct roles for rna interference and gut microbiota.arboviruses are transmitted by mosquitoes and other arthropods to humans and animals. the risk associated with these viruses is increasing worldwide, including new emergence in europe and the americas. anopheline mosquitoes are vectors of human malaria but are believed to transmit one known arbovirus, o'nyong-nyong virus, whereas aedes mosquitoes transmit many. anopheles interactions with viruses have been little studied, and the initial antiviral response in the midgut has not been examined. he ...201425548172
upon intranasal vesicular stomatitis virus infection, astrocytes in the olfactory bulb are important interferon beta producers that protect from lethal encephalitis.previously we found that following intranasal (i.n.) infection with neurotropic vesicular stomatitis virus (vsv) type i interferon receptor (ifnar) triggering of neuroectodermal cells was critically required to constrain intracerebral virus spread. to address whether locally active ifn-β was induced proximally, we studied spatiotemporal conditions of vsv-mediated ifn-β induction. to this end, we performed infection studies with ifn-β reporter mice. one day after intravenous (i.v.) vsv infection, ...201425540366
deficiency in either 4e-bp1 or 4e-bp2 augments innate antiviral immune responses.genetic deletion of both 4e-bp1 and 4e-bp2 was found to protect cells against viral infections. here we demonstrate that the individual loss of either 4e-bp1 or 4e-bp2 in mouse embryonic fibroblasts (mefs) is sufficient to confer viral resistance. shrna-mediated silencing of 4e-bp1 or 4e-bp2 renders mefs resistant to viruses, and compared to wild type cells, mefs knockout for either 4e-bp1 or 4e-bp2 exhibit enhanced translation of irf-7 and consequently increased innate immune response to viruse ...201425531441
enhancing and initiating phage-based therapies.drug development has typically been a primary foundation of strategy for systematic, long-range management of pathogenic cells. however, drug development is limited in speed and flexibility when response is needed to changes in pathogenic cells, especially changes that produce drug-resistance. the high replication speed and high diversity of phages are potentially useful for increasing both response speed and response flexibility when changes occur in either drug resistance or other aspects of p ...201426713220
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
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
virus-host interactomics: new insights and opportunities for antiviral drug discovery.the current therapeutic arsenal against viral infections remains limited, with often poor efficacy and incomplete coverage, and appears inadequate to face the emergence of drug resistance. our understanding of viral biology and pathophysiology and our ability to develop a more effective antiviral arsenal would greatly benefit from a more comprehensive picture of the events that lead to viral replication and associated symptoms. towards this goal, the construction of virus-host interactomes is in ...201425593595
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
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
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
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
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
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
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
macroautophagy proteins assist epstein barr virus production and get incorporated into the virus particles.epstein barr virus (ebv) persists as a latent herpes virus infection in the majority of the adult human population. the virus can reactivate from this latent infection into lytic replication for virus particle production. here, we report that autophagic membranes, which engulf cytoplasmic constituents during macroautophagy and transport them to lysosomal degradation, are stabilized by lytic ebv replication in infected epithelial and b cells. inhibition of autophagic membrane formation compromise ...201426137519
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
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
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
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
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