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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
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
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
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
novel indole-2-carboxamide compounds are potent broad-spectrum antivirals active against western equine encephalitis virus in vivo.neurotropic alphaviruses, including western, eastern, and venezuelan equine encephalitis viruses, cause serious and potentially fatal central nervous system infections in humans for which no currently approved therapies exist. we previously identified a series of thieno[3,2-b]pyrrole derivatives as novel inhibitors of neurotropic alphavirus replication, using a cell-based phenotypic assay (w. peng et al., j. infect. dis. 199:950-957, 2009, doi:http://dx.doi.org/10.1086/597275), and subsequently ...201425031353
expanding the proteome of an rna virus by phosphorylation of an intrinsically disordered viral protein.the human proteome contains myriad intrinsically disordered proteins. within intrinsically disordered proteins, polyproline-ii motifs are often located near sites of phosphorylation. we have used an unconventional experimental paradigm to discover that phosphorylation by protein kinase a (pka) occurs in the intrinsically disordered domain of hepatitis c virus non-structural protein 5a (ns5a) on thr-2332 near one of its polyproline-ii motifs. phosphorylation shifts the conformational ensemble of ...201425031324
a cationic nanoemulsion for the delivery of next-generation rna vaccines.nucleic acid-based vaccines such as viral vectors, plasmid dna, and mrna are being developed as a means to address a number of unmet medical needs that current vaccine technologies have been unable to address. here, we describe a cationic nanoemulsion (cne) delivery system developed to deliver a self-amplifying mrna vaccine. this nonviral delivery system is based on novartis's proprietary adjuvant mf59, which has an established clinical safety profile and is well tolerated in children, adults, a ...201425027661
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
a 6k-deletion variant of salmonid alphavirus is non-viable but can be rescued through rna recombination.pancreas disease (pd) of atlantic salmon is an emerging disease caused by salmonid alphavirus (sav) which mainly affects salmonid aquaculture in western europe. although genome structure of sav has been characterized and each individual viral protein has been identified, the role of 6k protein in viral replication and infectivity remains undefined. the 6k protein of alphaviruses is a small and hydrophobic protein which is involved in membrane permeabilization, protein processing and virus buddin ...201425009976
age-dependent myeloid dendritic cell responses mediate resistance to la crosse virus-induced neurological disease.la crosse virus (lacv) is the major cause of pediatric viral encephalitis in the united states; however, the mechanisms responsible for age-related susceptibility in the pediatric population are not well understood. our current studies in a mouse model of lacv infection indicated that differences in myeloid dendritic cell (mdc) responses between weanling and adult mice accounted for susceptibility to lacv-induced neurological disease. we found that type i interferon (ifn) responses were signific ...201425008929
applications of in vivo imaging in the evaluation of the pathophysiology of viral and bacterial infections and in development of countermeasures to bsl3/4 pathogens.while preclinical and clinical imaging have been applied to drug discovery/development and characterization of disease pathology, few examples exist where imaging has been used to evaluate infectious agents or countermeasures to biosafety level (bsl)3/4 threat agents. viruses engineered with reporter constructs, i.e., enzymes and receptors, which are amenable to detection by positron emission tomography (pet), single photon emission tomography (spect), or magnetic resonance imaging (mri) have be ...201425008802
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
jatropha gossypiifolia l. (euphorbiaceae): a review of traditional uses, phytochemistry, pharmacology, and toxicology of this medicinal plant.jatropha gossypiifolia l. (euphorbiaceae), widely known as "bellyache bush," is a medicinal plant largely used throughout africa and america. several human and veterinary uses in traditional medicine are described for different parts and preparations based on this plant. however, critical reviews discussing emphatically its medicinal value are missing. this review aims to provide an up-to-date overview of the traditional uses, as well as the phytochemistry, pharmacology, and toxicity data of j. ...201425002902
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
discovery of a novel compound with anti-venezuelan equine encephalitis virus activity that targets the nonstructural protein 2.alphaviruses present serious health threats as emerging and re-emerging viruses. venezuelan equine encephalitis virus (veev), a new world alphavirus, can cause encephalitis in humans and horses, but there are no therapeutics for treatment. to date, compounds reported as anti-veev or anti-alphavirus inhibitors have shown moderate activity. to discover new classes of anti-veev inhibitors with novel viral targets, we used a high-throughput screen based on the measurement of cell protection from liv ...201424967809
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
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
host factors that interact with the pestivirus n-terminal protease, npro, are components of the ribonucleoprotein complex.the viral n-terminal protease n(pro) of pestiviruses counteracts cellular antiviral defenses through inhibition of irf3. here we used mass spectrometry to identify a new role for n(pro) through its interaction with over 55 associated proteins, mainly ribosomal proteins and ribonucleoproteins, including rna helicase a (dhx9), y-box binding protein (ybx1), ddx3, ddx5, eif3, igf2bp1, multiple myeloma tumor protein 2, interleukin enhancer binding factor 3 (iebp3), guanine nucleotide binding protein ...201424965446
undiagnosed acute viral febrile illnesses, sierra leone.sierra leone in west africa is in a lassa fever-hyperendemic region that also includes guinea and liberia. each year, suspected lassa fever cases result in submission of ≈500-700 samples to the kenema government hospital lassa diagnostic laboratory in eastern sierra leone. generally only 30%-40% of samples tested are positive for lassa virus (lasv) antigen and/or lasv-specific igm; thus, 60%-70% of these patients have acute diseases of unknown origin. to investigate what other arthropod-borne an ...024959946
antiviral perspectives for chikungunya virus.chikungunya virus (chikv) is a mosquito-borne pathogen that has a major health impact in humans and causes acute febrile illness in humans accompanied by joint pains and, in many cases, persistent arthralgia lasting for weeks to years. chikv reemerged in 2005-2006 in several parts of the indian ocean islands and india after a gap of 32 years, causing millions of cases. the re-emergence of chikv has also resulted in numerous outbreaks in several countries in the eastern hemisphere, with a threat ...201424955364
exploration of panviral proteome: high-throughput cloning and functional implications in virus-host interactions.throughout the long history of virus-host co-evolution, viruses have developed delicate strategies to facilitate their invasion and replication of their genome, while silencing the host immune responses through various mechanisms. the systematic characterization of viral protein-host interactions would yield invaluable information in the understanding of viral invasion/evasion, diagnosis and therapeutic treatment of a viral infection, and mechanisms of host biology. with more than 2,000 viral ge ...201424955142
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
high efficiency of alphaviral gene transfer in combination with 5-fluorouracil in a mouse mammary tumor model.the combination of virotherapy and chemotherapy may enable efficient tumor regression that would be unachievable using either therapy alone. in this study, we investigated the efficiency of transgene delivery and the cytotoxic effects of alphaviral vector in combination with 5-fluorouracil (5-fu) in a mouse mammary tumor model (4 t1).201424950740
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
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
dominance effects of deleterious and beneficial mutations in a single gene of the rna virus ϕ6.most of our knowledge of dominance stems from studies of deleterious mutations. from these studies we know that most deleterious mutations are recessive, and that this recessivity arises from a hyperbolic relationship between protein function (i.e., protein concentration or activity) and fitness. here we investigate whether this knowledge can be used to make predictions about the dominance of beneficial and deleterious mutations in a single gene. we employed a model system--the bacteriophage φ6- ...201424945910
alphavirus-based vaccines.alphavirus vectors have demonstrated high levels of transient heterologous gene expression both in vitro and in vivo and, therefore, possess attractive features for vaccine development. the most commonly used delivery vectors are based on three single-stranded encapsulated alphaviruses, namely semliki forest virus, sindbis virus and venezuelan equine encephalitis virus. alphavirus vectors have been applied as replication-deficient recombinant viral particles and, more recently, as replication-pr ...201424937089
jatrophane diterpenes as inhibitors of chikungunya virus replication: structure-activity relationship and discovery of a potent lead.bioassay-guided purification of an etoac extract of the whole plant of euphorbia amygdaloides ssp. semiperfoliata using a chikungunya virus-cell-based assay led to the isolation of six new (1-4, 9, and 10) and six known (5-7, 8, 11, and 12) jatrophane esters. their planar structures and relative configurations were determined by extensive spectroscopic analysis, and their absolute configurations by x-ray analysis. these compounds were investigated for selective antiviral activity against chikung ...201424926807
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
locking and blocking the viral landscape of an alphavirus with neutralizing antibodies.alphaviruses are serious, sometimes lethal human pathogens that belong to the family togaviridae. the structures of human venezuelan equine encephalitis virus (veev), an alphavirus, in complex with two strongly neutralizing antibody fab fragments (f5 and 3b4c-4) have been determined using a combination of cryo-electron microscopy and homology modeling. we characterize these monoclonal antibody fab fragments, which are known to abrogate veev infectivity by binding to the e2 (envelope) surface gly ...201424920796
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
gas chromatography-mass spectroscopy analysis of bioactive petalostigma extracts: toxicity, antibacterial and antiviral activities.petalostigma pubescens and petalostigma triloculare were common components of pharmacopeia's of multiple australian aboriginal tribal groupings which traditionally inhabited the areas in which they grow. among these groups, they had a myriad of medicinal uses in treating a wide variety of bacterial, fungal and viral infections. this study was undertaken to test p. pubescens and p. triloculare leaf and fruit extracts for the ability to inhibit bacterial and viral growth and thus validate australi ...201424914307
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
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
unfolded protein response in hepatitis c virus infection.hepatitis c virus (hcv) is a single-stranded, positive-sense rna virus of clinical importance. the virus establishes a chronic infection and can progress from chronic hepatitis, steatosis to fibrosis, cirrhosis, and hepatocellular carcinoma (hcc). the mechanisms of viral persistence and pathogenesis are poorly understood. recently the unfolded protein response (upr), a cellular homeostatic response to endoplasmic reticulum (er) stress, has emerged to be a major contributing factor in many human ...201424904547
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
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
an alphavirus-based adjuvant enhances serum and mucosal antibodies, t cells, and protective immunity to influenza virus in neonatal mice.neonatal immune responses to infection and vaccination are biased toward th2 at the cost of proinflammatory th1 responses needed to combat intracellular pathogens. however, upon appropriate stimulation, the neonatal immune system can induce adult-like th1 responses. here we report that a new class of vaccine adjuvant is especially well suited to enhance early life immunity. the gvi3000 adjuvant is a safe, nonpropagating, truncated derivative of venezuelan equine encephalitis virus that targets d ...201424899195
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
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
genetically engineered mice as experimental tools to dissect the critical events in breast cancer.elucidating the mechanism of pathogenesis of breast cancer has greatly benefited from breakthrough advances in both genetically engineered mouse (gem) models and xenograft transplantation technologies. the vast array of breast cancer mouse models currently available is testimony to the complexity of mammary tumorigenesis and attempts by investigators to accurately portray the heterogeneity and intricacies of this disease. distinct molecular changes that drive various aspects of tumorigenesis, su ...024889535
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
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
model-driven engineering of gene expression from rna replicons.rna replicons are an emerging platform for engineering synthetic biological systems. replicons self-amplify, can provide persistent high-level expression of proteins even from a small initial dose, and, unlike dna vectors, pose minimal risk of chromosomal integration. however, no quantitative model sufficient for engineering levels of protein expression from such replicon systems currently exists. here, we aim to enable the engineering of multigene expression from more than one species of replic ...201524877739
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
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
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
buggy creek virus (togaviridae: alphavirus) upregulates expression of pattern recognition receptors and interferons in house sparrows (passer domesticus).birds serve as reservoirs for at least 10 arthropod-borne viruses, yet specific immune responses of birds to arboviral infections are relatively unknown. here, adult house sparrows were inoculated with an arboviral alphavirus, buggy creek virus (bcrv), or saline, and euthanized between 1 and 3 days postinoculation. virological dynamics and gene expression dynamics were investigated. birds did not develop viremia postinoculation, but cytopathic virus was found in the skeletal muscle and spleen of ...201424866749
distribution of protein poly(adp-ribosyl)ation systems across all domains of life.poly(adp-ribosyl)ation is a post-translational modification of proteins involved in regulation of many cellular pathways. poly(adp-ribose) (par) consists of chains of repeating adp-ribose nucleotide units and is synthesized by the family of enzymes called poly(adp-ribose) polymerases (parps). this modification can be removed by the hydrolytic action of poly(adp-ribose) glycohydrolase (parg) and adp-ribosylhydrolase 3 (arh3). hydrolytic activity of macrodomain proteins (macrod1, macrod2 and targ1 ...201424865146
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
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
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
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
current strategic thinking for the development of a trivalent alphavirus vaccine for human use.vaccinations against the encephalitic alphaviruses (western, eastern, and venezuelan equine encephalitis virus) are of significant interest to biological defense, public health, and agricultural communities alike. although vaccines licensed for veterinary applications are used in the western hemisphere and attenuated or inactivated viruses have been used under investigational new drug status to protect at-risk personnel, there are currently no licensed vaccines for use in humans. here, we will d ...201424842880
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
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
type-i interferons suppress microglial production of the lymphoid chemokine, cxcl13.lymphoid chemokines are crucial for the development and maintenance of lymphoid organs, but their ectopic expression in non-lymphoid tissues is implicated in both local response to infection and chronic organ-specific autoimmunity. production of one such chemokine, c-x-c motif ligand 13 (cxcl13), within the central nervous system (cns) has been linked to the pathogenesis of multiple sclerosis (ms), although little is known about factors controlling its expression in different neural cell types a ...201424829092
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
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
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
replication of many human viruses is refractory to inhibition by endogenous cellular micrornas.the issue of whether viruses are subject to restriction by endogenous micrornas (mirnas) and/or by virus-induced small interfering rnas (sirnas) in infected human somatic cells has been controversial. here, we address this question in two ways. first, using deep sequencing, we demonstrate that infection of human cells by the rna virus dengue virus (denv) or west nile virus (wnv) does not result in the production of any virus-derived sirnas or viral mirnas. second, to more globally assess the pot ...201424807715
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
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
a small molecule inhibits virion attachment to heparan sulfate- or sialic acid-containing glycans.primary attachment to cellular glycans is a critical entry step for most human viruses. some viruses, such as herpes simplex virus type 1 (hsv-1) and hepatitis c virus (hcv), bind to heparan sulfate, whereas others, such as influenza a virus (iav), bind to sialic acid. receptor mimetics that interfere with these interactions are active against viruses that bind to either heparan sulfate or to sialic acid. however, no molecule that inhibits the attachment of viruses in both groups has yet been id ...201424789779
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
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
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
identification of sphingomyelinase on the surface of chlamydia pneumoniae: possible role in the entry into its host cells.we have recently suggested a novel mechanism, autoendocytosis, for the entry of certain microbes into their hosts, with a key role played by the sphingomyelinase-catalyzed topical conversion of sphingomyelin to ceramide, the differences in the biophysical properties of these two lipids providing the driving force. the only requirement for such microbes to utilize this mechanism is that they should have a catalytically active smase on their outer surface while the target cells should expose sphin ...201424757444
plant virus expression vector development: new perspectives.plant made biologics have elicited much attention over recent years for their potential in assisting those in developing countries who have poor access to modern medicine. additional applications such as the stockpiling of vaccines against pandemic infectious diseases or potential biological warfare agents are also under investigation. plant virus expression vectors represent a technology that enables high levels of pharmaceutical proteins to be produced in a very short period of time. recent ad ...201424745025
arthritogenic alphaviral infection perturbs osteoblast function and triggers pathologic bone loss.arthritogenic alphaviruses including ross river virus (rrv), sindbis virus, and chikungunya virus cause worldwide outbreaks of musculoskeletal disease. the ability of alphaviruses to induce bone pathologies remains poorly defined. here we show that primary human osteoblasts (hobs) can be productively infected by rrv. rrv-infected hobs produced high levels of inflammatory cytokine including il-6. the rankl/opg ratio was disrupted in the synovial fluid of rrv patients, and this was accompanied by ...201424733914
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
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
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
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
enhanced production of chikungunya virus-like particles using a high-ph adapted spodoptera frugiperda insect cell line.chikungunya virus-like particles (vlps) have potential to be used as a prophylactic vaccine based on testing in multiple animal models and are currently being evaluated for human use in a phase i clinical trial. the current method for producing these enveloped alphavirus vlps by transient gene expression in mammalian cells presents challenges for scalable and robust industrial manufacturing, so the insect cell baculovirus expression vector system was evaluated as an alternative expression techno ...201424713807
interferon-stimulated genes: roles in viral pathogenesis.interferon-stimulated genes (isgs) are critical for controlling virus infections. as new antiviral isgs continue to be identified and characterized, their roles in viral pathogenesis are also being explored in more detail. our current understanding of how isgs impact viral pathogenesis comes largely from studies in knockout mice, with isolated examples from human clinical data. this review outlines recent developments on the contributions of various isgs to viral disease outcomes in vivo.201424713352
synapto-depressive effects of amyloid beta require pick1.amyloid beta (aβ), a key component in the pathophysiology of alzheimer's disease, is thought to target excitatory synapses early in the disease. however, the mechanism by which aβ weakens synapses is not well understood. here we showed that the pdz domain protein, protein interacting with c kinase 1 (pick1), was required for aβ to weaken synapses. in mice lacking pick1, elevations of aβ failed to depress synaptic transmission in cultured brain slices. in dissociated cultured neurons, aβ failed t ...024713001
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
regulation of the autophagic bcl-2/beclin 1 interaction.autophagy is an intracellular degradation process responsible for the delivery of cellular material to the lysosomes. one of the key mechanisms for control of autophagy is the modulation of the interaction between the autophagic protein beclin 1 and the members of the anti-apoptotic bcl-2 family (e.g., bcl-2, bcl-xl and mcl-1). this binding is regulated by a variety of proteins and compounds that are able to enhance or inhibit the bcl-2/beclin 1 interaction in order to repress or activate autoph ...201224710477
divergent roles of autophagy in virus infection.viruses have played an important role in human evolution and have evolved diverse strategies to co-exist with their hosts. as obligate intracellular pathogens, viruses exploit and manipulate different host cell processes, including cellular trafficking, metabolism and immunity-related functions, for their own survival. in this article, we review evidence for how autophagy, a highly conserved cellular degradative pathway, serves either as an antiviral defense mechanism or, alternatively, as a pro ...201324709646
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
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
ebolavirus entry requires a compact hydrophobic fist at the tip of the fusion loop.ebolavirus is an enveloped virus causing severe hemorrhagic fever. its surface glycoproteins undergo proteolytic cleavage and rearrangements to permit membrane fusion and cell entry. here we focus on the glycoprotein's internal fusion loop (fl), critical for low-ph-triggered fusion in the endosome. alanine mutations at l529 and i544 and particularly the l529 i544 double mutation compromised viral entry and fusion. the nuclear magnetic resonance (nmr) structures of the i544a and l529a i544a mutan ...201424696482
ccr2 deficiency promotes exacerbated chronic erosive neutrophil-dominated chikungunya virus arthritis.chikungunya virus (chikv) is a member of a globally distributed group of arthritogenic alphaviruses that cause weeks to months of debilitating polyarthritis/arthralgia, which is often poorly managed with current treatments. arthritic disease is usually characterized by high levels of the chemokine ccl2 and a prodigious monocyte/macrophage infiltrate. several inhibitors of ccl2 and its receptor ccr2 are in development and may find application for treatment of certain inflammatory conditions, incl ...201424696480
characterizing functional domains for tim-mediated enveloped virus entry.t-cell immunoglobulin and mucin domain 1 (tim-1) and other tim family members were recently identified as phosphatidylserine (ptdser)-mediated virus entry-enhancing receptors (pveers). these proteins enhance entry of ebola virus (ebov) and other viruses by binding ptdser on the viral envelope, concentrating virus on the cell surface, and promoting subsequent internalization. the ptdser-binding activity of the immunoglobulin-like variable (igv) domain is essential for both virus binding and inter ...201424696470
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
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
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