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il-10 restricts memory t cell inflation during cytomegalovirus infection.the beta-herpesvirus cmv induces a substantial and progressive expansion of virus-specific memory cd8 t cells, which protect the host against viral reactivation from latency. in this paper, we report that this expansion, or "inflation," of memory t cells is amplified dramatically during mouse cmv infection of il-10 knockout (il-10(-/-)) mice. t cells from il-10(-/-) mice were oligoclonal, exhibited a highly activated phenotype, expressed antiviral cytokines, and degranulated in response to cogna ...201020713884
interleukin-10 repletion suppresses pro-inflammatory cytokines and decreases liver pathology without altering viral replication in murine cytomegalovirus (mcmv)-infected il-10 knockout mice.to determine the role of interleukin-10 (il-10) in protecting against the deleterious pro-inflammatory cytokine response to murine cytomegalovirus (mcmv), we studied the impact of il-10 repletion in mcmv-infected il-10 knockout (ko) mice.201020922456
in vivo impact of cytomegalovirus evasion of cd8 t-cell immunity: facts and thoughts based on murine models.cytomegaloviruses (cmvs) co-exist with their respective host species and have evolved to avoid their elimination by the hosts' immune effector mechanisms and to persist in a non-replicative state, known as viral latency. there is evidence to suggest that latency is nevertheless a highly dynamic condition during which episodes of viral gene desilencing, which can be viewed as incomplete reactivations, cause intermittent antigenic activity that stimulates cd8 memory-effector t cells and drives the ...201020933556
inhibition of programmed cell death by cytomegaloviruses.the elimination of infected cells by programmed cell death (pcd) is one of the most ancestral defense mechanisms against infectious agents. this mechanism should be most effective against intracellular parasites, such as viruses, which depend on the host cell for their replication. however, even large and slowly replicating viruses like the cytomegaloviruses (cmvs) can prevail and persist in face of cellular suicide programs and other innate defense mechanisms. during evolution, these viruses ha ...201020969904
cathepsin c limits acute viral infection independently of nk cell and cd8(+) t-cell cytolytic function.destruction of target cells by cytotoxic t lymphocytes (ctls) or natural killer (nk) cells requires the coordinated action of the pore forming protein perforin (pfp) and the granzyme (gzm) family of serine proteases. the activation of a number of serine proteases, including gzma and b, is predominately mediated by cathepsin c (catc). deficiencies in catc-null mice were therefore expected to replicate the defects observed in gzmab-deficient mice. we have previously determined that gzmab-deficient ...201020975734
cytomegalovirus immunoevasin reveals the physiological role of "missing self" recognition in natural killer cell dependent virus control in vivo.cytomegaloviruses (cmvs) are renowned for interfering with the immune system of their hosts. to sidestep antigen presentation and destruction by cd8(+) t cells, these viruses reduce expression of major histocompatibility complex class i (mhc i) molecules. however, this process sensitizes the virus-infected cells to natural killer (nk) cell-mediated killing via the "missing self" axis. mouse cytomegalovirus (mcmv) uses m152 and m06 encoded proteins to inhibit surface expression of mhc i molecules ...201021078887
[role of allitridin in the blocking of murine cytomegalovirus induced regulatory t cells amplification in vitro].to investigate the effect of allitridin on murine cytomegalovirus (mcmv) induced regulatory t cells (treg) amplification in vitro.201020979868
the role of decay accelerating factor in the immunopathogenesis of cytomegalovirus infection.a wide variety of the host immune elements play an influential role in the defence against cytomegalovirus (cmv) infection. however, the role of complement in the clearance of cmv infection is less well studied. decay accelerating factor (daf/cd55) is a membrane-bound complement regulatory protein that inhibits the formation and accelerates the decay of c3-convertase. here we hypothesize that murine cmv (mcmv) utilizes daf as an immunoevasive strategy through down-regulation of host adaptive res ...201021166665
comparative analysis of the lambda-interferons il-28a and il-29 regarding their transcriptome and their antiviral properties against hepatitis c virus.specific differences in signaling and antiviral properties between the different lambda-interferons, a novel group of interferons composed of il-28a, il-28b and il-29, are currently unknown. this is the first study comparatively investigating the transcriptome and the antiviral properties of the lambda-interferons il-28a and il-29.201021170333
functional consequences of natural sequence variation of murine cytomegalovirus m157 for ly49 receptor specificity and nk cell activation.the ly49h activating receptor on c57bl/6 (b6) nk cells plays a key role in early resistance to murine cytomegalovirus (mcmv) infection through specific recognition of the mcmv-encoded mhc class i-like molecule m157 expressed on infected cells. the m157 molecule is also recognized by the ly49i inhibitory receptor from the 129/j mouse strain. the m157 gene is highly sequence variable among mcmv isolates, with many m157 variants unable to bind ly49h(b6). in this study, we have sought to define if m ...201021187440
antiviral prevention of sepsis induced cytomegalovirus reactivation in immunocompetent mice.immunocompetent patients can reactivate latent cytomegalovirus (cmv) during critical illness and reactivation is associated with significantly worse outcomes. prior to clinical trials in humans to prove causality, we sought to determine an optimal antiviral treatment strategy.201020004216
stability of murine cytomegalovirus genome after in vitro and in vivo passage.while large dna viruses are thought to have low mutation rates, only a small fraction of their genomes have been analyzed at the single-nucleotide level. here, we defined the genetic stability of murine cytomegalovirus (mcmv) by whole-genome sequencing. independently assembled sequences of three sister plaques showed only two single-base-pair substitutions after in vitro passage. in vivo-passaged mcmv likewise demonstrated low mutation rates, comparable to those after in vitro passage, indicatin ...201020015993
immune evasion proteins of murine cytomegalovirus preferentially affect cell surface display of recently generated peptide presentation complexes.for recognition of infected cells by cd8 t cells, antigenic peptides are presented at the cell surface, bound to major histocompatibility complex class i (mhc-i) molecules. downmodulation of cell surface mhc-i molecules is regarded as a hallmark function of cytomegalovirus-encoded immunoevasins. the molecular mechanisms by which immunoevasins interfere with the mhc-i pathway suggest, however, that this downmodulation may be secondary to an interruption of turnover replenishment and that hindranc ...201019906905
deletion of the rat cytomegalovirus immediate-early 1 gene results in a virus capable of establishing latency, but with lower levels of acute virus replication and latency that compromise reactivation efficiency.the immediate-early 1 (ie1) and ie2 proteins encoded by the major immediate-early (mie) transcription unit of cytomegaloviruses are thought to play key roles in the switch between latent- and lytic-cycle infection. whilst ie2 is essential for triggering the lytic cycle, the exact roles of ie1 have not been resolved. an mie-exon 4-deleted rat cytomegalovirus (deltaie1) failed to synthesize the ie1 protein and did not disperse promyelocytic leukaemia bodies early post-infection, but was still capa ...201019923265
catalytic m1gs rna as an antiviral agent in animals.the use of rnase p ribozyme (m1gs catalytic rna) for inhibition of murine cytomegalovirus (mcmv) propagation in mice is described in this chapter. general information about rnase p based technology is included and followed by detailed protocols focused on (1) construction and in vitro cleavage assay of the customized m1gs ribozyme, (2) stable expression of the m1gs rna and evaluation of its activity in inhibition of viral gene expression and growth in cultured cells, and (3) investigation of m1g ...201020387160
virus inhibition of rip3-dependent necrosis.viral infection activates cytokine expression and triggers cell death, the modulation of which is important for successful pathogenesis. necroptosis is a form of programmed necrosis dependent on two related rip homotypic interaction motif (rhim)-containing signaling adaptors, receptor-interacting protein kinases (rip) 1 and 3. we find that murine cytomegalovirus infection induces rip3-dependent necrosis. whereas rip3 kinase activity and rhim-dependent interactions control virus-associated necros ...201020413098
a novel transmembrane domain mediating retention of a highly motile herpesvirus glycoprotein in the endoplasmic reticulum.gene m164 of murine cytomegalovirus belongs to the large group of 'private' genes that show no homology to those of other cytomegalovirus species and are thought to represent 'host adaptation' genes involved in virus-host interaction. previous interest in the m164 gene product was based on the presence of an immunodominant cd8 t-cell epitope presented at the surface of infected cells, despite interference by viral immune-evasion proteins. here, we provide data to reveal that the m164 gene produc ...201020147515
direct interaction of the mouse cytomegalovirus m152/gp40 immunoevasin with rae-1 isoforms.cytomegaloviruses (cmvs) are ubiquitous species-specific viruses that establish acute, persistent, and latent infections. both human and mouse cmvs encode proteins that inhibit the activation of natural killer (nk) cells by downregulating cellular ligands for the nk cell activating receptor, nkg2d. the mcmv glycoprotein m152/gp40 downregulates the surface expression of rae-1 to prevent nk cell control in vivo. so far, it is unclear if there is a direct interaction between m152 and rae-1 and, if ...201020166740
biphasic role of 4-1bb in the regulation of mouse cytomegalovirus-specific cd8(+) t cells.the initial requirement for the emergence of cmv-specific cd8(+) t cells is poorly understood. mice deficient in the cosignaling tnf superfamily member, 4-1bb, surprisingly developed exaggerated early cd8(+) t-cell responses to mouse cmv (mcmv). cd8(+) t cells directed against acute mcmv epitopes were enhanced, demonstrating that 4-1bb naturally antagonizes these primary populations. paradoxically, 4-1bb-deficient mice displayed reduced accumulation of memory cd8(+) t cells that expand during ch ...201020722077
endoplasmic reticulum aminopeptidase associated with antigen processing defines the composition and structure of mhc class i peptide repertoire in normal and virus-infected cells.the mhc class i (mhc-i) molecules ferry a cargo of peptides to the cell surface as potential ligands for cd8(+) cytotoxic t cells. for nearly 20 years, the cargo has been described as a collection of short 8-9 mer peptides, whose length and sequences were believed to be primarily determined by the peptide-binding groove of mhc-i molecules. yet the mechanisms for producing peptides of such optimal length and composition have remained unclear. in this study, using mass spectrometry, we determined ...201020173027
the m74 gene product of murine cytomegalovirus (mcmv) is a functional homolog of human cmv go and determines the entry pathway of mcmv.the glycoprotein go (ul74) of human cytomegalovirus (hcmv) forms a complex with gh/gl. virus mutants with a deletion of go show a defect in secondary envelopment with the consequence that virus spread is restricted to a cell-associated pathway. here we report that the positional homolog of hcmv go, m74 of mouse cmv (mcmv), codes for a glycosylated protein which also forms a complex with gh (m75). m74 knockout mutants of mcmv show the same spread phenotype as go knockout mutants of hcmv, namely, ...201020181688
contribution of tlr7 and tlr9 signaling to the susceptibility of myd88-deficient mice to myocarditis.toll-like receptors (tlrs) are evolutionary conserved molecules that recognize various microbial components and host-derived agonists from damaged cells and play a central role in innate and adaptive immunity. it has been reported that myd88, the adaptor molecule downstream of all tlrs, except tlr3, is essential for initiation of experimental autoimmune myocarditis (eam). to determine the role of the intracellular tlrs in eam, tlr3(-/-), tlr7(-/-), and tlr9(-/-) mice were immunized with cardiac ...201020187710
cross-presentation of a spread-defective mcmv is sufficient to prime the majority of virus-specific cd8+ t cells.cd8+ t cells can be primed by peptides derived from endogenous proteins (direct presentation), or exogenously acquired protein (cross-presentation). however, the relative ability of these two pathways to prime cd8+ t cells during a viral infection remains controversial. cytomegaloviruses (cmvs) can infect professional antigen presenting cells (apcs), including dendritic cells, thus providing peptides for direct presentation. however, the viral immune evasion genes profoundly impair recognition o ...201020300633
occult cytomegalovirus in vivarium-housed mice may influence transplant allograft acceptance.we have recently shown that latent murine cytomegalovirus (mcmv) can influence murine transplant allograft acceptance. during these studies we became aware that vivarium-housed control mice can acquire occult mcmv infection. the purpose of this investigation was to confirm occult mcmv transmission and determine the timing, vehicle, and possible consequences of transmission. mice arriving from a commercial vendor were negative for mcmv both by commercial serologic testing and by our nested pcr. m ...201020307665
caspases in virus-infected cells contribute to recognition by cd8+ t lymphocytes.cd8(+) cytotoxic t lymphocytes recognize infected cells in which mhc class i molecules present pathogen-derived peptides that have been processed mainly by proteasomes. many infections induce a set of proteases, the caspases involved in apoptosis or inflammation. in this study, we report that processing and presentation of a short vaccinia virus-encoded ag can take place also by a nonproteasomal pathway, which was blocked in infected cells with chemical inhibitors of caspases. by cleaving at non ...201020348426
rapamycin-resistant mtorc1 kinase activity is required for herpesvirus replication.human cytomegalovirus (hcmv) infection has been shown to activate the mtorc1 signaling pathway. however, the phosphorylation of mtorc1 targets is differentially sensitive to the mtorc1 inhibitor rapamycin, and the drug inhibits hcmv replication to a modest extent. using torin1, a newly developed inhibitor that targets the catalytic site of mtor kinase, we show that hcmv replication requires both rapamycin-sensitive and rapamycin-resistant mtor activity. the treatment of infected cells with torin ...201020181700
the nk receptor klrg1 is dispensable for virus-induced nk and cd8+ t-cell differentiation and function in vivo.the killer cell lectin-like receptor g1 (klrg1) is expressed by nk and t-cell subsets and recognizes members of the classical cadherin family. klrg1 is widely used as a lymphocyte differentiation marker in both humans and mice but the physiological role of klrg1 in vivo is still unclear. here, we generated klrg1-deficient mice by homologous recombination and used several infection models for their characterization. the results revealed that klrg1 deficiency did not affect development and functio ...201020201037
promoter control over foreign antigen expression in a murine cytomegalovirus vaccine vector.previous studies have reported on the development of a recombinant murine cytomegalovirus (rmcmv) containing the mouse zona pellucida 3 (mzp3) gene for use as a virally vectored immunocontraceptive (vvic). this study aimed to alter promoter control over foreign antigen expression and cellular localisation of the antigen expressed in order to overcome virus attenuation previously encountered. early studies reported on the mzp3 gene expressed by a strong constitutive human cytomegalovirus immediat ...201020338212
functional plasticity and robustness are essential characteristics of biological systems: lessons learned from klrg1-deficient mice.killer cell lectin-like receptor g1 (klrg1) receptor is considered to be a marker of terminally differentiated nk and t cells and is strongly induced by viral and other infections. klrg1 is a c-type lectin-like inhibitory receptor, which interacts with members of the cadherin family of molecules leading to the inhibition of t- and nk-cell function. a study in this issue of the european journal of immunology addresses the role of klrg1 in the maturation and differentiation of nk and t cells in vi ...201020373518
virally infected mouse liver endothelial cells trigger cd8+ t-cell immunity.dendritic cell activation through ligation of pattern recognition receptors leading to full functional maturation causes induction of cd8(+) t-cell immunity through increased delivery of costimulatory signals instead of tolerance. here we investigate whether organ-resident antigen-presenting cells, such as liver sinusoidal endothelial cells (lsecs), also switch from tolerogenic to immunogenic cd8(+) t-cell activation upon such stimulation.201019737567
cytomegalovirus microrna expression is tissue specific and is associated with persistence.micrornas (mirnas) are a class of small noncoding rnas involved in posttranscriptional regulation. mirnas are utilized in organisms ranging from plants to higher mammals, and data have shown that dna viruses also use this method for host and viral gene regulation. here, we report the sequencing of the small rnas in rat cytomegalovirus (rcmv)-infected fibroblasts and persistently infected salivary glands. we identified 24 unique mirnas that mapped to hairpin structures found within the viral geno ...201020980502
b7-mediated costimulation of cd4 t cells constrains cytomegalovirus persistence.cytomegalovirus (cmv) utilizes multiple strategies to modulate immunity and promote lifelong, persistent/latent infection, including suppressing t cell activation pathways. here we examined the role of b7 costimulatory ligands in establishing immune détente from both the host and virus perspectives. mice lacking both b7.1 and b7.2 showed reduced early expansion of cmv-specific cd4 t cells, consequently allowing for enhanced levels of persistent virus replication. in turn, a cmv mutant lacking ex ...201020980516
recombinant mouse cytomegalovirus expressing a ligand for the nkg2d receptor is attenuated and has improved vaccine properties.human cmv (hcmv) is a major cause of morbidity and mortality in both congenitally infected and immunocompromised individuals. development of an effective hcmv vaccine would help protect these vulnerable groups. nk group 2, member d (nkg2d) is a potent activating receptor expressed by cells of the innate and adaptive immune systems. its importance in hcmv immune surveillance is indicated by the elaborative evasion mechanisms evolved by the virus to avoid nkg2d. in order to study this signaling pa ...201021099111
the activator protein 1 binding motifs within the human cytomegalovirus major immediate-early enhancer are functionally redundant and act in a cooperative manner with the nf-{kappa}b sites during acute infection.human cytomegalovirus (hcmv) infection causes a rapid induction of c-fos and c-jun, the major subunits of activator protein 1 (ap-1), which in turn have been postulated to activate the viral immediate-early (ie) genes. accordingly, the major ie promoter (miep) enhancer, a critical control region for initiating lytic hcmv infection and reactivation from the latent state, contains one well-characterized ap-1 site and a second candidate interaction site. in this study we explored the role of these ...201021106746
plasmacytoid dendritic cell ablation impacts early interferon responses and antiviral nk and cd8(+) t cell accrual.plasmacytoid dendritic cells (pdcs) mediate type i interferon (ifn-i) responses to viruses that are recognized through the toll-like receptor 7 (tlr7) or tlr9 signaling pathway. however, it is unclear how pdcs regulate the antiviral responses via innate and adaptive immune cells. we generated diphtheria toxin receptor transgenic mice to selectively deplete pdcs by administration of diphtheria toxin. pdc-depleted mice were challenged with viruses known to activate pdcs. in murine cytomegalovirus ...201021130004
[fluvastatin's effect on atherogenesis in apolipoprotein-e knockout mice infected by cytomegalovirus].the goal of this study was to investigate whether murine cytomegalovirus (mcmv) is able to exacerbate the atherosclerotic process in apolipoprotein e knockout (apoe -/-) mice, and the effect of fluvastatin on the atherogenesis.201021604568
can we build it better? using bac genetics to engineer more effective cytomegalovirus vaccines.the magnitude and durability of immunity to human cytomegalovirus (hcmv) following natural infection is compromised by the presence of immune modulation genes that appear to promote evasion of host clearance mechanisms. since immunity to hcmv offers limited protection, rational design of effective vaccines has been challenging. in this issue of the jci, slavuljica and colleagues employ techniques to genetically modify the highly related mouse cmv (mcmv), in the process generating a virus that wa ...201021099107
murine cytomegalovirus us22 protein pm140 protects its binding partner, pm141, from proteasome-dependent but ubiquitin-independent degradation.stable assembly of murine cytomegalovirus (mcmv) virions in differentiated macrophages is dependent upon the expression of us22 family gene m140. the m140 protein (pm140) exists in complex with products of neighboring us22 genes. here we report that pm140 protects its binding partner, pm141, from ubiquitin-independent proteasomal degradation. protection is conferred by a stabilization domain mapping to amino acids 306 to 380 within pm140, and this domain is functionally independent from the regi ...201019955315
in vivo imaging of ocular mcmv infection.to develop a technique by which murine cytomegalovirus (mcmv) infection can be confirmed and monitored in vivo in various ocular compartments and to investigate the dynamics and time course of primary ocular cmv infection.201019684003
lack of tnf-alpha promotes caspase-3-independent apoptosis during murine cytomegalovirus retinitis.both caspase-dependent and caspase-independent apoptosis contribute to retinal damage during murine cytomegalovirus (mcmv) retinitis, and tnf-a is among the inducers of apoptosis. the aim of this study was to determine the contribution of tnf-a by studying virus replication and apoptosis in immunosuppressed (is) tnf-a(-/-) mice.201121310911
salivary gland nk cells are phenotypically and functionally unique.natural killer (nk) cells and cd8(+) t cells play vital roles in containing and eliminating systemic cytomegalovirus (cmv). however, cmv has a tropism for the salivary gland acinar epithelial cells and persists in this organ for several weeks after primary infection. here we characterize a distinct nk cell population that resides in the salivary gland, uncommon to any described to date, expressing both mature and immature nk cell markers. using rorγt reporter mice and nude mice, we also show tha ...201121249177
activation receptor-induced tolerance of mature nk cells in vivo requires signaling through the receptor and is reversible.nk cell responses are determined by signals received through activating and inhibitory cell surface receptors. ly49h is an nk cell-specific activating receptor that accounts for the genetic resistance to murine cmv (mcmv). the ly49h receptor has been shown to interact with two adaptor proteins (dap12 and dap10). in the context of mcmv infection, interaction of m157 (the mcmv-encoded ligand for ly49h) with ly49h results in activation of ly49h-expressing nk cells. chronic exposure of ly49h with m1 ...201121263069
host defense against viral infection involves interferon mediated down-regulation of sterol biosynthesis.little is known about the protective role of inflammatory processes in modulating lipid metabolism in infection. here we report an intimate link between the innate immune response to infection and regulation of the sterol metabolic network characterized by down-regulation of sterol biosynthesis by an interferon regulatory loop mechanism. in time-series experiments profiling genome-wide lipid-associated gene expression of macrophages, we show a selective and coordinated negative regulation of the ...201121408089
cytomegalovirus-induced sensorineural hearing loss with persistent cochlear inflammation in neonatal mice.congenital cytomegalovirus (cmv) infection is the leading cause of sensorineural hearing loss (snhl) in children. during murine (m)cmv-induced encephalitis, the immune response is important for both the control of viral dissemination and the clearance of virus from the brain. while the importance of cmv-induced snhl has been described, the mechanisms surrounding its pathogenesis and the role of inflammatory responses remain unclear. this study presents a neonatal mouse model of profound snhl in ...201121416394
self mhc class i-licensed nk cells enhance adaptive cd8 t-cell viral immunity.mhc class i (mhc i) is essential to nk- and t-cell effector and surveillance functions. however, it is unknown whether mhc i polymorphism influences adaptive immunity through nk cells. previously, we found that mhc i d(k), a cognate ligand for the ly49g2 inhibitory receptor, was essential to nk control of murine (m)cmv infection. here we assessed the significance of nk inhibitory receptor recognition of mcmv on cd8 t cells in genetically defined mhc i d(k) disparate mice. we observed that d(k)-l ...201121436069
[a murine model with murine cytomegalovirus infection resulting in colon inflammation after allogenetic skin transplantation].to provide a reliable animal model for study of human cmv disease in gastrointestinal track, we tried to infect with murine cytomegalovirus (mcmv) in mice that were received allogenetic skin transplantation under immunosuppression. (1) skin transplantation was performed between 18 donor c57bl/6 mice and 72 recipient balb/c mice. (2) all recipient mice were then given cyclosporine at 12 mg/kg daily for 2 weeks by intraperitoneal injection. mice were randomly divided into 3 groups. two experimenta ...201121462500
p-selectin mediates the microvascular dysfunction associated with persistent cytomegalovirus infection in normocholesterolemic and hypercholesterolemic mice.please cite this paper as: senchenkov, khoretonenko, leskov, ostanin, and stokes (2011). p-selectin mediates the microvascular dysfunction associated with persistent cytomegalovirus infection in normocholesterolemic and hypercholesterolemic mice. microcirculation 18(6), 452-462. abstract: objective: cytomegalovirus has been implicated in cardiovascular disease, possibly through the induction of inflammatory processes. p-selectin and l-selectin are adhesion molecules that mediate early microvasc ...201121457388
absence of vasoactive intestinal peptide expression in hematopoietic cells enhances th1 polarization and antiviral immunity in mice.vasoactive intestinal peptide (vip) induces regulatory dendritic cells (dc) in vitro that inhibit cellular immune responses. we tested the role of physiological levels of vip on immune responses to murine cmv (mcmv) using vip-knockout (vip-ko) mice and radiation chimeras engrafted with syngenic vip-ko hematopoietic cells. vip-ko mice had less weight loss and better survival following mcmv infection compared with wild-type (wt) littermates. mcmv-infected vip-ko mice had lower viral loads, faster ...201121677142
antigen-presenting cells of hematopoietic origin prime cytomegalovirus-specific cd8 t cells but are not sufficient for driving memory inflation during viral latency.expansion of the cd8 t cell memory pool, also known as 'memory inflation', for certain but not all viral epitopes in latently infected host tissues is a special feature of the immune response to cytomegalovirus. the ld-presented murine cytomegalovirus (mcmv) ie1 peptide is the prototype of an epitope that is associated with memory inflation. based on the detection of ie1 transcripts in latently infected lungs it was previously proposed that episodes of viral gene expression and antigenic activit ...201121632567
Expression of the RAE-1 family of stimulatory NK-cell ligands requires activation of the PI3K pathway during viral infection and transformation.Natural killer (NK) cells are lymphocytes that play a major role in the elimination of virally-infected cells and tumor cells. NK cells recognize and target abnormal cells through activation of stimulatory receptors such as NKG2D. NKG2D ligands are self-proteins, which are absent or expressed at low levels on healthy cells but are induced upon cellular stress, transformation, or viral infection. The exact molecular mechanisms driving expression of these ligands remain poorly understood. Here we ...201121966273
il-10 restricts activation-induced death of nk cells during acute murine cytomegalovirus infection.il-10 is an immunomodulatory cytokine that acts to antagonize t cell responses elicited during acute and chronic infections. thus, the il-10r signaling pathway provides a potential therapeutic target in strategies aimed at combating infectious diseases. in this study, we set out to investigate whether il-10 expression had an effect on nk cells. murine cmv infection provides the best characterized in vivo system to evaluate the nk cell response, with nk cells being critical in the early control o ...201121849677
Flagellin, a TLR5 agonist, reduces graft-versus-host disease in allogeneic hematopoietic stem cell transplantation recipients while enhancing antiviral immunity.Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in patients treated with allogeneic hematopoietic stem cell transplantation (HSCT). Posttransplant immunosuppressive drugs incompletely control GVHD and increase susceptibility to opportunistic infections. In this study, we used flagellin, a TLR5 agonist protein (~50 kDa) extracted from bacterial flagella, as a novel experimental treatment strategy to reduce both acute and chronic GVHD in allogeneic HSCT recipients. On ...201122013117
h2b homology region of major immediate-early (mie) protein 1 (ie1) is essential for murine cytomegalovirus to disrupt nuclear domain 10 (nd10), but not important for viral replication in cell culture.abstract: cytomegalovirus (cmv) major immediate-early protein 1 (ie1) has multiple functions and is important for efficient viral infection. as does its counterpart in human cmv, murine cmv (mcmv) ie1 also functions as a disruptor of mouse cell nd10 (nuclear domain 10), where many different gene-regulation proteins congregate. it still remains unclear how mcmv ie1 disperses nd10 and whether this dispersion could have any effect on viral replication. mcmv ie1 has 595 amino acids and multiple func ...201121632568
suppression of tlr9 immunostimulatory motifs in the genome of a gammaherpesvirus.multiple receptors within the innate immune system have evolved to recognize nucleic acids as signatures of viral infection. it is believed that this specificity is essential for viral detection, as viruses often lack other invariant features that can serve as suitable targets for innate receptors. one such innate receptor, tlr9, has been implicated in the detection of many dsdna viruses. in this study, we investigate the detection of murine gammaherpesvirus 68 (mhv68) by tlr9. we find that the ...201121666062
A replicating cytomegalovirus-based vaccine encoding a single Ebola virus nucleoprotein CTL epitope confers protection against Ebola virus.Human outbreaks of Ebola virus (EBOV) are a serious human health concern in Central Africa. Great apes (gorillas/chimpanzees) are an important source of EBOV transmission to humans due to increased hunting of wildlife including the 'bush-meat' trade. Cytomegalovirus (CMV) is an highly immunogenic virus that has shown recent utility as a vaccine platform. CMV-based vaccines also have the unique potential to re-infect and disseminate through target populations regardless of prior CMV immunity, whi ...201121858240
cytomegalovirus e127 protein interacts with the inhibitory cd200 receptor.cd200 is a cell surface glycoprotein that binds an inhibitory receptor (cd200r) on myeloid cells. cd200 orthologues are present in many species of virus, and we show that the rat cytomegalovirus cd200 orthologue (e127) is expressed at the cell surface on infected cells. it binds the host cd200r with the same affinity as that of the host protein, and thus this protein acts as a close mimic of the host protein and has the potential to downregulate immune responses to the virus.201121471232
comparing the kinetics of nk cells, cd4, and cd8 t cells in murine cytomegalovirus infection.nk cells recognize virus-infected cells with germline-encoded activating and inhibitory receptors that do not undergo genetic recombination or mutation. accordingly, nk cells are often considered part of the innate immune response. the innate response comprises rapid early defenders that do not form immune memory. however, there is increasing evidence that experienced nk cells provide increased protection to secondary infection, a hallmark of the adaptive response. in this study, we compare the ...201121697462
virus progeny of mcmv bacterial artificial chromosome psm3fr shows reduced growth in salivary glands due to a fixed mutation of mck-2.mcmv (murine cytomegalovirus) smith strain has been cloned as a bacterial artificial chromosome (bac) named psm3fr and has since then been used for analysis of virus gene functions in vitro and in vivo. when sequencing the complete bac genome, we identified a frameshift mutation within the orf encoding mcmv chemokine homolog mck-2. this mutation would result in a truncated mck-2 protein. when mice were infected with psm3fr-derived virus, we observed a reduced virus production in salivary glands ...201121813614
reversible inhibition of mcmv replication by ifn{gamma} in primary macrophages involves a primed type i ifn signaling sub-network for full establishment of an immediate-early antiviral-state.activated macrophages play a central role in controlling inflammatory responses to infection and are tightly regulated to rapidly mount responses to infectious challenge. type-i (ifna/ß) and type-ii (ifn?) interferon play a crucial role in activating macrophages and subsequently restricting viral infections. both types of ifns signal through related but distinct signaling pathways, inducing a vast number of interferon stimulated genes, overlapping but distinguishable. the exact mechanism by whic ...201121775459
temporal profiling of the coding and noncoding murine cytomegalovirus transcriptomes.the global transcriptional program of murine cytomegalovirus (mcmv), involving coding, noncoding, and antisense transcription, remains unknown. here we report an oligonucleotide custom microarray platform capable of measuring both coding and noncoding transcription on a genome-wide scale. by profiling mcmv wild-type and immediate-early mutant strains in fibroblasts, we found rapid activation of the transcriptome by 6.5 h postinfection, with absolute dependency on ie3, but not ie1 or ie2, for gen ...201121471238
partial functional complementation between human and mouse cytomegalovirus chemokine receptor homologues.the human cytomegalovirus (cmv) proteins us28 and ul33 are homologous to chemokine receptors (ckrs). knockout of the mouse cmv m33 protein (ul33 homologue) results in substantial attenuation of salivary gland infection/replication and reduced efficiency of reactivation from tissue explants. m33-mediated g protein-coupled signaling is critical for the salivary gland phenotype. in this report, we demonstrate that us28 and (to a lesser degree) ul33 restore reactivation from tissue explants and part ...201121490099
distinct mhc class i-dependent nk cell-activating receptors control cytomegalovirus infection in different mouse strains.recognition of mouse cytomegalovirus (mcmv)-infected cells by activating nk cell receptors was first described in the context of ly49h, which confers resistance to c57bl/6 mice. we investigated the ability of other activating ly49 receptors to recognize mcmv-infected cells in mice from various h-2 backgrounds. we observed that ly49p1 from nod/ltj mice, ly49l from balb mice, and ly49d2 from pwk/pas mice respond to mcmv-infected cells in the context of h-2d(k) and the viral protein m04/gp34. recog ...201121518798
nk cell receptor/h2-d-dependent host resistance to viral infection is quantitatively modulated by h2 inhibitory signals.the cytomegalovirus resistance locus cmv3 has been linked to an epistatic interaction between two loci: a natural killer (nk) cell receptor gene and the major histocompatibility complex class i (mhc-i) locus. to demonstrate the interaction between cmv3 and h2(k), we generated double congenic mice between ma/my and balb.k mice and an f(2) cross between fvb/n (h-2(q)) and balb.k (h2(k)) mice, two strains susceptible to mouse cytomegalovirus (mcmv). only mice expressing h2(k) in conjunction with cm ...201121533075
t cell responses in experimental viral retinitis: mechanisms, peculiarities and implications for gene therapy with viral vectors.t lymphocytes play a decisive role in the course and clinical outcome of viral retinal infection. this review focuses on aspects of the adaptive cellular immune response against viral pathogens in the retina. two distinct models to study adaptive cell mediated immune responses in viral retinitis are presented: (i) experimental retinitis induced by murine cytomegalovirus (mcmv), where the immune system prevents necrotizing damage to the retina and (ii) retinitis induced by the non-cytopathic lymp ...201121550416
functional interaction of nuclear domain 10 and its components with cytomegalovirus after infections: cross-species host cells versus native cells.species-specificity is one of the major characteristics of cytomegaloviruses (cmvs) and is the primary reason for the lack of a mouse model for the direct infection of human cmv (hcmv). it has been determined that cmv cross-species infections are blocked at the post-entry level by intrinsic cellular defense mechanisms, but few details are known. it is important to explore how cmvs interact with the subnuclear structure of the cross-species host cell. in our present study, we discovered that nucl ...201121552525
small molecule inhibitors of the host cell cox/areg/egfr/erk pathway attenuate cytomegalovirus-induced pathogenesis.as with other herpesviruses, human cytomegalovirus (hcmv) has the ability to establish lifelong persistence and latent infection following primary exposure, salivary glands (smgs) being the primary site of both. in the immunocompromised patient, hcmv is a common cause of opportunistic infections, and subsequent morbidity and mortality. elucidating the molecular pathogenesis of cmv-induced disease is critical to the development of more effective and safer drug therapies. in the present study, we ...201121565184
m94 is essential for the secondary envelopment of murine cytomegalovirus.the gene m94 of murine cytomegalovirus (mcmv) as well as its homologues ul16 in alphaherpesviruses is involved in viral morphogenesis. for a better understanding of its role in the viral life cycle, a library of random m94 mutants was generated by modified transposon-based linker scanning mutagenesis. a comprehensive set of m94 mutants was reinserted into the mcmv genome and tested for their capacity to complement the m94 null mutant. thereby, 34 loss-of-function mutants of m94 were identified, ...201121715482
t cell help permits memory cd8(+) t cell inflation during cytomegalovirus latency.cd4(+) t cells are implied to sustain cd8(+) t cell responses during persistent infections. as cd4(+) t cells are often themselves antiviral effectors, they might shape cd8(+) t cell responses via help or via controlling antigen load. we used persistent mouse cytomegalovirus (mcmv) infection to dissect the impact of cd4(+) t cells on virus-specific cd8(+) t cells, distinguishing between increased viral load in absence of cd4(+) t cells and cd4(+) t cell-mediated helper mechanisms. absence of t h ...201121590767
effects of allitridin on acute and chronic mouse cytomegalovirus infection.this study investigated the effects of allitridin on acute and chronic mouse cytomegalovirus (mcmv) infections in vivo. the results demonstrated that allitridin reduced the titers of mcmv in salivary glands, and reductions in viral loads were confirmed by determining viral dna and rna levels in susceptible organs during the acute infection phase. although allitridin did not eliminate mcmv, treatment reduced viral levels and facilitated healing of pathologic lesions in organs, particularly during ...201121604182
batf3 transcription factor-dependent dc subsets in murine cmv infection: differential impact on t cell priming and memory inflation.priming of cd8(+) t cells specific for viruses that interfere with the mhc class i presentation pathway is a challenge for the immune system and is believed to rely on cross-presentation. cytomegalovirus (cmv) infection induces vigorous cd8(+) t cell responses despite its potent immune evasion strategies. furthermore, cd8(+) t cells specific for a subset of viral epitopes accumulate and are maintained at high levels exhibiting an activated phenotype - referred to as 'inflationary t cells'. takin ...201121604258
the role of interleukin-17 in murine cytomegalovirus interstitial pneumonia in mice with skin transplants.we hypothesized that the t helper (th)17 response plays an important role in murine cytomegalovirus (mcmv) interstitial pneumonia. balb/c mice with skin grafts from c57/bj6 mice were intranasally inoculated with 1.0 × 10(5) pfu mcmv. lung tissues and skin grafts were histologically evaluated and expression of interleukins (il)-17, -6 and -8, monocyte chemotactic protein (mcp)-1 and interferon (ifn)-γ in serum and bronchoalveolar lavage (bal) fluid, intracellular il-4, -17, and ifn-γ, in spleen l ...201121623953
expression and iron-dependent regulation of succinate receptor gpr91 in retinal pigment epithelium.gpr91, a succinate receptor, is expressed in retinal ganglion cells and induces vascular endothelial growth factor (vegf) expression. rpe also expresses vegf, but whether this cell expresses gpr91 is not known. excessive iron is also proangiogenic, and hemochromatosis is associated with iron overload. therefore, we examined the expression and iron-dependent regulation of gpr91 in the rpe.201121357408
mouse embryonic stem cells inhibit murine cytomegalovirus infection through a multi-step process.in humans, cytomegalovirus (cmv) is the most significant infectious cause of intrauterine infections that cause congenital anomalies of the central nervous system. currently, it is not known how this process is affected by the timing of infection and the susceptibility of early-gestational-period cells. embryonic stem (es) cells are more resistant to cmv than most other cell types, although the mechanism responsible for this resistance is not well understood. using a plaque assay and evaluation ...201121407806
the mouse cytomegalovirus glycoprotein m155 inhibits cd40 expression and restricts cd4 t cell responses.cytomegaloviruses (cmv) utilize a variety of immunomodulatory strategies to facilitate the establishment of lifelong persistence in their infected hosts. we show that the mouse cmv (mcmv) m155 open reading frame (orf) is required for the posttranscriptional inhibition of cd40 expression in infected antigen-presenting cells. consistent with the known importance of cd40-mediated costimulation of t cells, a m155-deficient virus induces enhanced mcmv epitope-specific cd4 t cell responses.201121411536
virus-induced differential expression of nuclear receptors and coregulators in dendritic cells: implication to interferon production.we investigated mrna expression of 49 nuclear hormone receptors (nrs) and 35 transcriptional coregulators in mouse bone marrow-derived dendritic cells (dcs) upon infection with newcastle disease virus (ndv) or murine cytomegalovirus (mcmv). these viruses regulated mrna expression of some nrs among which nor1 and lxrα were highly induced at mrna and protein levels. exogenous expression of the latter nrs repressed irf3- or irf7-induced transactivation of the interferon β promoter and ndv infection ...201121492741
dissecting the requirements for maintenance of the cmv-specific memory t-cell pool.cytomegalovirus (cmv) infection promotes a broad t-cell response, with the resulting memory cells displaying diverse phenotypes. cmv establishes lifelong persistence/latency, and it is thought that viral antigens expressed during this period may regulate the expansion and/or maintenance of "inflationary" cd8 t-memory populations that display an effector memory phenotype. we show here that mouse cmv (mcmv)-specific inflationary memory t cells do not decrease in number after thymectomy, indicating ...201121721929
Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential.Antiviral compounds that increase the resistance of host tissues represent an attractive class of therapeutic. Here, we show that squalamine, a compound previously isolated from the tissues of the dogfish shark (Squalus acanthias) and the sea lamprey (Petromyzon marinus), exhibits broad-spectrum antiviral activity against human pathogens, which were studied in vitro as well as in vivo. Both RNA- and DNA-enveloped viruses are shown to be susceptible. The proposed mechanism involves the capacity o ...201121930925
ganciclovir transiently attenuates murine cytomegalovirus-associated renal allograft inflammation.prophylactic ganciclovir (gcv) is used in high-risk renal transplant patients to prevent acute cytomegalovirus (cmv) disease, but its impact on inflammation within the allograft itself remains undefined.201121878840
[influence of allitridin on transcription, expression and function of il-12 genes in mice infected by murine cytomegalovirus].to investigate whether allitridin could interfere with the effects of murine cytomegalovirus (mcmv) infection on the transcription, expression and function of il-12 genes in order to further explore the mechanism of allitridin against mcmv.201122007556
absence of cross-presenting cells in the salivary gland and viral immune evasion confine cytomegalovirus immune control to effector cd4 t cells.horizontal transmission of cytomegaloviruses (cmv) occurs via prolonged excretion from mucosal surfaces. we used murine cmv (mcmv) infection to investigate the mechanisms of immune control in secretory organs. cd4 t cells were crucial to cease mcmv replication in the salivary gland (sg) via direct secretion of ifnγ that initiated antiviral signaling on non-hematopoietic cells. in contrast, cd4 t cell helper functions for cd8 t cells or b cells were dispensable. despite sg-resident mcmv-specific ...201121901102
virally-induced upregulation of heparan sulfate on b cells via the action of type i ifn.cell surface heparan sulfate (hs) is an important coreceptor for many cytokines, chemokines, and growth factors. in this study, we report that splenic murine b cells express very little hs and that upon infection with either gammaherpesvirus (murine gammaherpesvirus 68) or betaherpesvirus (murine cytomegalovirus), hs is rapidly upregulated at the surface of b cells. hs upregulation was not observed in mice deficient for the type i ifn (ifn-i) receptor. additionally, treatment of wild-type mice w ...201122048770
polarized distribution of heme transporters in retinal pigment epithelium and their regulation in the iron-overload disease hemochromatosis.flvcr, bcrp, and pcft/hcp-1 represent the three heme transporters identified thus far in mammalian cells, but there is very little known about their expression and regulation in the retina. in this study, the expression of these transporters in mouse retina and retinal pigment epithelium (rpe) and their regulation in the iron-overload disease hemochromatosis were examined.201122058337
impact of β2 integrin deficiency on mouse natural killer cell development and function.natural killer (nk) cells are innate immune cells that express members of the leukocyte β2 integrin family in humans and mice. these cd11/cd18 heterodimers play critical roles in leukocyte trafficking, immune synapse formation, and costimulation. the cell-surface expression of one of these integrins, cd11b/cd18, is also recognized as a major marker of mouse nk-cell maturation, but its function on nk cells has been largely ignored. using n-ethyl-n-nitrosourea (enu) mutagenesis, we generated a mou ...201121239699
differential requirements for cd45 in nk-cell function reveal distinct roles for syk-family kinases.the protein tyrosine phosphatase cd45 is an important regulator of src-family kinase activity. we found that in the absence of cd45, natural killer (nk) cells are defective in protecting the host from mouse cytomegalovirus infection. we show that although cd45 is necessary for all immunoreceptor tyrosine-based activation motif (itam)-specific nk-cell functions and processes such as degranulation, cytokine production, and expansion during viral infection, the impact of cd45 deficiency on itam sig ...201121245479
murine cytomegalovirus infection of neural stem cells alters neurogenesis in the developing brain.congenital cytomegalovirus (cmv) brain infection causes serious neuro-developmental sequelae including: mental retardation, cerebral palsy, and sensorineural hearing loss. but, the mechanisms of injury and pathogenesis to the fetal brain are not completely understood. the present study addresses potential pathogenic mechanisms by which this virus injures the cns using a neonatal mouse model that mirrors congenital brain infection. this investigation focused on, analysis of cell types infected wi ...201121249143
murine model for congenital cmv infection and hearing impairment.congenital cytomegalovirus (cmv) infection is the leading cause of sensorineural hearing loss (snhl), and snhl is the most frequent sequela of congenital cmv infection. but the pathogenic mechanism remains unknown, and there is no ideal cmv intrauterine infection animal model to study the mechanisms by which snhl develops.201121320351
single cell detection of latent cytomegalovirus reactivation in host tissue.the molecular mechanisms leading to reactivation of latent cytomegalovirus are not well understood. to study reactivation, the few cells in an organ tissue that give rise to reactivated virus need to be identified, ideally at the earliest possible time point in the process. to this end, mouse cytomegalovirus (mcmv) reporter mutants were designed to simultaneously express the red fluorescent protein mcherry and the secreted gaussia luciferase (gluc). whereas gluc can serve to assess infection at ...201121325477
salivary glands act as mucosal inductive sites via the formation of ectopic germinal centers after site-restricted mcmv infection.we investigated the hypothesis that salivary gland inoculation stimulates formation of ectopic germinal centers (gcs), transforming the gland into a mucosal inductive site. intraglandular infection of mice with murine cytomegalovirus (mcmv; control: uv-inactivated mcmv) induces salivary gland ectopic follicles comprising cognate interactions between cd4(+) and b220(+) lymphocytes, igm(+) and isotype-switched igg(+) and iga(+) b cells, antigen presenting cells, and follicular dendritic cells. b c ...201121307334
differential b7-cd28 costimulatory requirements for stable and inflationary mouse cytomegalovirus-specific memory cd8 t cell populations.cmv establishes a lifelong persistent infection, and viral immune-modulating strategies are important in facilitating this. a particularly diverse cd8 t cell response develops as a result of this host-virus détente, with the cmv-specific memory t cell pool displaying unique functions and phenotypes. to gain insight into the factors that regulate cmv-specific cd8 t cell responses, we examined the influence of the b7-cd28 costimulatory pathway on magnitude, kinetics, and phenotype. initial expansi ...201121357256
genetic labeling reveals altered turnover and stability of innate lymphocytes in latent mouse cytomegalovirus infection.mouse cmv (mcmv) infection rapidly induces the proliferation of nk cells, which correlates with immunological protection. whether nk cells primed during acute response against mcmv are maintained for the long term is not known. in this study, we used tcrdh2begfp mice in which maturing nk cells are genetically labeled with a pulse of very stable histone-2b-egfp. in this system, we found that the reporter protein was diluted out upon nk cell division during acute mcmv infection. at the same time, ...201121270406
transmission of murine cytomegalovirus in breast milk: a model of natural infection in neonates.vertical transmission of viruses in breast milk can expose neonates to infectious pathogens at a time when the capacity of their immune system to control infections is limited. we developed a mouse model to study the outcomes of acquisition of murine cytomegalovirus (mcmv) when neonates are breastfed by mothers with acute or latent infection. breast milk leukocytes collected from lactating mice were examined for the presence of mcmv ie-1 mrna by reverse transcription-pcr (rt-pcr) with southern a ...201121367905
exploitation of herpesviral transactivation allows quantitative reporter gene-based assessment of virus entry and neutralization.herpesviral entry is a highly elaborated process requiring many proteins to act in precise conjunction. neutralizing antibodies interfere with this process to abrogate viral infection. based on promoter transactivation of a reporter gene we established a novel method to quantify herpesvirus entry and neutralization by antibodies. following infection with mouse and human cytomegalovirus and herpes simplex virus 1 we observed promoter transactivation resulting in substantial luciferase expression ...201121264213
human herpesvirus 7 in allogeneic hemopoietic stem cell transplant recipients in the central clinical hospital in warsaw: a three-year survey.human herpesvirus 7 (hhv-7) is spread worldwide and has been described as a potential pathogen in immunosuppressed patients. different clinical manifestations have been described including fever and skin rash; hhv-7 may also be a possible cofactor for cytomegalovirus disease in transplant recipients.201120689313
a dominant role for the immunoproteasome in cd8+ t cell responses to murine cytomegalovirus.murine cytomegalovirus (mcmv) is an important animal model of human cytomegalovirus (hcmv), a ß-herpesvirus that infects the majority of the world's population and causes disease in neonates and immunocompromised adults. cd8(+) t cells are a major part of the immune response to mcmv and hcmv. processing of peptides for presentation to cd8(+) t cells may be critically dependent on the immunoproteasome, expression of which is affected by mcmv. however, the overall importance of the immunoproteasom ...201121304910
tuning of natural killer cell reactivity by nkp46 and helios calibrates t cell responses.natural killer (nk) cells are lymphocytes involved in antimicrobial and antitumoral immune responses. using n-ethyl-n-nitrosourea mutagenesis in mice, we identified a mutant with increased resistance to viral infections because of the presence of hyperresponsive nk cells. whole-genome sequencing and functional analysis revealed a loss-of-function mutation in the ncr1 gene encoding the activating receptor nkp46. the down-regulation of nk cell activity by nkp46 was associated with the silencing of ...201222267813
Natural Killer Cell Licensing During Viral Infection.Natural Killer (NK) cell functionality is controlled by inhibitory receptors that recognize self-MHC class I. NK cells that do not interact with self-MHC class I are hypo-responsive to many stimuli and fail to reject MHC class I-deficient cells. Thus, although the mechanisms are unknown, interactions with MHC class I "licensed" NK cells respond efficiently. Surprisingly, these licensed NK cells fail to control viral infection. During mouse cytomegalovirus (MCMV) infection, SHP-1 signaling downst ...201221842363
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