Publications

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mice with a selective impairment of ifn-gamma signaling in macrophage lineage cells demonstrate the critical role of ifn-gamma-activated macrophages for the control of protozoan parasitic infections in vivo.ifn-gamma has long been recognized as a cytokine with potent and varied effects in the immune response. although its effects on specific cell types have been well studied in vitro, its in vivo effects are less clearly understood because of its diverse actions on many different cell types. although control of multiple protozoan parasites is thought to depend critically on the direct action of ifn-gamma on macrophages, this premise has never been directly proven in vivo. to more directly examine t ...201020018611
constitutive activation of wnt signaling favors generation of memory cd8 t cells.t cell factor-1 (tcf-1) and lymphoid enhancer-binding factor 1, the effector transcription factors of the canonical wnt pathway, are known to be critical for normal thymocyte development. however, it is largely unknown if it has a role in regulating mature t cell activation and t cell-mediated immune responses. in this study, we demonstrate that, like il-7ralpha and cd62l, tcf-1 and lymphoid enhancer-binding factor 1 exhibit dynamic expression changes during t cell responses, being highly expres ...201020026746
innate signaling regulates cross-priming at the level of dc licensing and not antigen presentation.innate stimuli, such as tlr ligands, are known to greatly facilitate cross-priming. currently it is unclear whether innate stimuli enhance cross-priming at the level of cross-presentation or at the level of t-cell priming. in this study, we addressed this question by measuring cross-presentation as well as cross-priming by virus-like particles (vlp) displaying peptide p33 derived of lymphocytic choriomeningitis virus. innate stimuli were varied by either packaging different tlr ligands into viru ...201019877013
on the role of the inhibitory receptor lag-3 in acute and chronic lcmv infection.chronic viral infections are often characterized by cd8 t-cell responses with poor cytokine secretion potential and limited expansion of the cd8 t-cell pool, collectively referred to as cd8 t-cell exhaustion. exhaustion of lymphocytic choriomeningitis virus (lcmv)-specific cd8 t cells was shown to be partially regulated by the inhibitory receptor programmed death 1 (pd-1). here, we demonstrate that exhausted lcmv-specific cd8 t cells also express the negative regulatory receptor lymphocyte activ ...201019880580
translating insights from persistent lcmv infection into anti-hiv immunity.human immunodeficiency virus (hiv) is a major global health concern with more than 30 million individuals currently infected worldwide. to date, attempts to stimulate protective immunity to viral components of hiv have been unsuccessful in preventing or clearing infection. lymphocytic choriomeningitis virus (lcmv) is an established murine model of persistent viral infection that has been instrumental in illuminating several critical aspects of antiviral immunity. although virologically the cours ...201020725865
bi-specific mhc heterodimers for characterization of cross-reactive t cells.t cell cross-reactivity describes the phenomenon whereby a single t cell can recognize two or more different peptide antigens presented in complex with mhc proteins. cross-reactive t cells have previously been characterized at the population level by cytokine secretion and mhc tetramer staining assays, but single-cell analysis is difficult or impossible using these methods. in this study, we describe development of a novel peptide-mhc heterodimer specific for cross-reactive t cells. mhc-peptide ...201020729210
homeostatic turnover of virus-specific memory cd8 t cells occurs stochastically and is independent of cd4 t cell help.memory cd8 t cells persist by ag-independent homeostatic proliferation. to examine the dynamics of this cell turnover, we transferred lymphocytic choriomeningitis virus specific memory cd8 t cells into naive mice and analyzed their in vivo division kinetics longitudinally in individual recipients.using mathematical modeling, we determined that proliferation of this stably maintained memory cd8 t cell population was homogeneous and stochastic with a small fraction of cells completing division at ...201020733203
genes determining the course of virus persistence in the liver: lessons from murine infection with lymphocytic choriomeningitis virus.more than 500 million people worldwide are persistently infected with either hepatitis b virus (hbv) or hepatitis c virus (hcv). although both viruses are poorly cytopathic, persistent infection causes severe immunopathologic damage to liver tissue; histologically, such damage is characterized by fatty liver disease, liver fibrosis, and a higher likelihood of hepatocellular carcinoma. virus-specific cd8+ t cells play a crucial role during infection with hepatitis viruses. on the one hand, rapid ...201020798510
regulation of memory cd8 t-cell differentiation by cyclin-dependent kinase inhibitor p27kip1.induction of potent t-cell memory is the goal of vaccinations, but the molecular mechanisms that regulate the formation of memory cd8 t cells are not well understood. despite the recognition that controls of cellular proliferation and apoptosis govern the number of memory t cells, the cell cycle regulatory mechanisms that control these key cellular processes in cd8 t cells during an immune response are poorly defined. here, we have identified the cyclin-dependent kinase inhibitor p27(kip1) as a ...201020805358
proline-rich tyrosine kinase-2 is critical for cd8 t-cell short-lived effector fate.t-cell interactions with antigen-presenting cells are important for cd8 t-cell effector or memory fate determination. the integrin leukocyte function-associated antigen-1 (lfa-1) mediates t-cell adhesion but the contribution of lfa-1-induced signaling pathways to t-cell responses is poorly understood. here we demonstrate that proline-rich tyrosine kinase-2 (pyk2) deficiency impairs cd8 t-cell activation by synergistic lfa-1 and t-cell receptor stimulation. furthermore, pyk2 is essential for lfa- ...201020805505
concomitant type i ifn receptor-triggering of t cells and of dc is required to promote maximal modified vaccinia virus ankara-induced t-cell expansion.virus-induced expansion of cd8(+) t cells may be promoted by type i ifn receptor (ifnar)-triggering of t cells, depending on the pathogen tested. we studied modified vaccinia virus ankara (mva), a promising vaccine vector candidate, which was derived from conventional vaccinia virus (vacv) by more than 570 consecutive in vitro passages. in adoptive transfer experiments, we verified that vacv expressing the gp33 epitope of lymphocytic choriomeningitis virus (vacv(gp33)) induced largely ifnar-inde ...201020821729
differential effects of stat5 and pi3k/akt signaling on effector and memory cd8 t-cell survival.during viral infection, effector cd8 t cells contract to form a population of protective memory cells that is maintained by il-7 and il-15. the mechanisms that control effector cell death during infection are poorly understood. we investigated how short- and long-lived antiviral cd8 t cells differentially used the survival and cell growth pathways pi3k/akt and jak/stat5. in response to il-15, long-lived memory precursor cells activated akt significantly better than short-lived effector cells. ho ...201020823247
chronic myelogenous leukemia maintains specific cd8(+) t cells through il-7 signaling.chronic myelogenous leukemia (cml) is a malignant myeloproliferative disease of hematopoietic stem cells. the disease progresses after several years from an initial chronic phase to a blast phase. leukemia-specific t cells are regularly detected in cml patients and may be involved in the immunological control of the disease. here, we analyzed the role of leukemia-specific cd8(+) t cells in cml disease control and the mechanism that maintains cd8(+) t-cell immunosurveillance in a retroviral-induc ...201020836157
il-21 deficiency influences cd8 t cell quality and recall responses following an acute viral infection.cd4 t cells are principal producers of il-21 and are often required for optimal cd8 t cell responses. therefore, we investigated the importance of il-21 in determining the phenotypic attributes, functional quality, and maintenance of antiviral cd8 t cells following acute infection with the prototypic mouse pathogen lymphocytic choriomeningitis virus. previous reports have documented an obligatory role for il-21 in sustaining cd8 t cell responses during chronic infections. here we show that the r ...201020844201
dendritic cell-specific antigen delivery by coronavirus vaccine vectors induces long-lasting protective antiviral and antitumor immunity.efficient vaccination against infectious agents and tumors depends on specific antigen targeting to dendritic cells (dcs). we report here that biosafe coronavirus-based vaccine vectors facilitate delivery of multiple antigens and immunostimulatory cytokines to professional antigen-presenting cells in vitro and in vivo. vaccine vectors based on heavily attenuated murine coronavirus genomes were generated to express epitopes from the lymphocytic choriomeningitis virus glycoprotein, or human melan- ...201020844609
t-cell receptor signals direct the composition and function of the memory cd8+ t-cell pool.sh2 domain-containing leukocyte phosphoprotein of 76 kda (slp-76) nucleates a signaling complex critical for t-cell receptor (tcr) signal propagation. mutations in the tyrosines of slp-76 result in graded defects in tcr-induced signals depending on the tyrosine(s) affected. here we use 2 strains of genomic knock-in mice expressing tyrosine to phenylalanine mutations to examine the role of tcr signals in the differentiation of effector and memory cd8(+) t cells in response to infection in vivo. o ...201020847203
the n-terminal domain of the arenavirus l protein is an rna endonuclease essential in mrna transcription.arenaviridae synthesize viral mrnas using short capped primers presumably acquired from cellular transcripts by a 'cap-snatching' mechanism. here, we report the crystal structure and functional characterization of the n-terminal 196 residues (nl1) of the l protein from the prototypic arenavirus: lymphocytic choriomeningitis virus. the nl1 domain is able to bind and cleave rna. the 2.13 å resolution crystal structure of nl1 reveals a type ii endonuclease α/β architecture similar to the n-terminal ...201020862324
reduced immunoproteasome formation and accumulation of immunoproteasomal precursors in the brains of lymphocytic choriomeningitis virus-infected mice.tissue inflammation is accompanied by the cytokine-mediated replacement of constitutive proteasomes by immunoproteasomes that finally leads to an optimized generation of mhc class i restricted epitopes for ag presentation. the brain is considered an immunoprivileged organ, where both the special anatomy as well as active tolerance mechanisms repress the development of inflammatory responses and help to prevent immunopathological damage. we analyzed the immunoproteasome expression in the brain af ...201020881186
dendritic cells recruit t cell exosomes via exosomal lfa-1 leading to inhibition of cd8+ ctl responses through downregulation of peptide/mhc class i and fas ligand-mediated cytotoxicity.active t cells release bioactive exosomes (exos). however, its potential modulation in immune responses is elusive. in this study, we in vitro generated active ova-specific cd8(+) t cells by cultivation of ova-pulsed dendritic cells (dc(ova)) with naive cd8(+) t cells derived from ova-specific tcr transgenic oti mice and purified exos from cd8(+) t cell culture supernatant by differential ultracentrifugation. we then investigated the suppressive effect of t cell exos on dc(ova)-mediated cd8(+) c ...201020881190
loss of tonic t-cell receptor signals alters the generation but not the persistence of cd8+ memory t cells.the requirements for tonic t-cell receptor (tcr) signaling in cd8(+) memory t-cell generation and homeostasis are poorly defined. the src homology 2 (sh2)-domain-containing leukocyte protein of 76 kda (slp-76) is critical for proximal tcr-generated signaling. we used temporally mediated deletion of slp-76 to interrupt tonic and activating tcr signals after clearance of the lymphocytic choriomeningitis virus (lcmv). slp-76-dependent signals are required during the contraction phase of the immune ...201020884806
egr-2 is not required for in vivo cd4 t cell mediated immune responses.the zinc finger transcription factor egr-2 has been shown to play an important role in the induction of t cell anergy and the regulation of peripheral t cell tolerance. in vitro, a prior study has show that t cells deficient in egr-2 are hyperproliferative to il-2 and produce elevated levels of the effector cytokine ifn-γ. egr-2 deficient mice have increased levels of cd44(high) t cells in peripheral lymphoid organs, and with age, develop autoimmune-like features.201020886122
pathogenic virus-specific t cells cause disease during treatment with the calcineurin inhibitor fk506: implications for transplantation.recently, several cases of fatal lymphocytic choriomeningitis virus (lcmv) infection occurred in transplant recipients being treated with the immunosuppressive calcineurin inhibitor fk506. these findings were surprising because lcmv is a noncytolytic virus. to understand how a noncytolytic virus can cause disease under conditions of immunosuppression, we used the mouse lcmv model and found that, similar to the observations in human transplant recipients, lcmv infection of fk506-treated mice resu ...201020921283
differential localization of effector and memory cd8 t cell subsets in lymphoid organs during acute viral infection.it is unclear where within tissues subsets of effector and memory cd8 t cells persist during viral infection and whether their localization affects function and long-term survival. following lymphocytic choriomeningitis virus infection, we found most killer cell lectin-like receptor g1 (klrg1)(lo)il-7r(hi) effector and memory cells, which are long-lived and high proliferative capacity, in the t cell zone of the spleen. in contrast, klrg1(hi)il-7r(lo) cells, which appear terminally differentiated ...201020921525
expression level of a pancreatic neo-antigen in beta cells determines degree of diabetes pathogenesis.it is not fully understood how the expression level of autoantigens in beta cells impacts autoimmune diabetes (t1d) development. earlier studies using ovalbumin and also insulin had shown that secreted antigens could enhance diabetes development through facilitated presentation by antigen presenting cells. here we sought to determine how the expression level of a membrane bound, non-secreted or cross-presented neo-antigen, the glycoprotein (gp) of lymphocytic choriomeningitis virus (lcmv), would ...201020932718
memory t cells are enriched in lymph nodes of selectin-ligand-deficient mice.fucosyltransferase-iv and -vii double knockout (ftdko) mice reveal profound impairment in t cell trafficking to lymph nodes (lns) due to an inability to synthesize selectin ligands. we observed an increase in the proportion of memory/effector (cd44(high)) t cells in lns of ftdko mice. we infected ftdko mice with lymphocytic choriomeningitis virus to generate and track ag-specific cd44(high)cd8 t cells in secondary lymphoid organs. although frequencies were similar, total ag-specific effector cd4 ...201020937846
lymphocytic choriomeningitis virus meningitis, new york, ny, usa, 2009.we describe a case of lymphocytic choriomeningitis virus (lcmv) meningitis in a new york, ny, resident who had no apparent risk factors. clues leading to the diagnosis included aseptic meningitis during winter and the finding of hypoglycorrachia and lymphocytosis in the cerebrospinal fluid. lcmv continues to be an underdiagnosed zoonotic disease.201020113573
altered immunodominance hierarchies of cd8+ t cells in the spleen after infection at different sites is contingent on high virus inoculum.activated epitope-specific cd8+ t cells after virus infection can be organized into hierarchies (immunodominance), based on their ability to focus the response on few viral determinants. the mechanisms responsible for immunodominance can be multifactorial, with cd8+ t cells precursor frequencies recently highlighted as a key regulator. employing the lcmv infection model, we demonstrate that the hierarchies were altered when comparing different sites of infection but only at high viral doses. the ...201020116444
il-10 directly suppresses cd4 but not cd8 t cell effector and memory responses following acute viral infection.mounting effective t cell responses is critical for eliciting long-lasting immunity following viral infection and vaccination. a multitude of inhibitory and stimulatory factors are induced following infection, and it is the compilation of these signals that quantitatively and qualitatively program the ensuing effector and memory t cell response. in response to lymphocytic choriomeningitis virus (lcmv) infection, the immunosuppressive cytokine il-10 is rapidly up-regulated; however, how il-10 is ...201020133700
development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent cd8+ t cell immunity.lymphocytic choriomeningitis virus (lcmv) exhibits natural tropism for dendritic cells and represents the prototypic infection that elicits protective cd8(+) t cell (cytotoxic t lymphocyte (ctl)) immunity. here we have harnessed the immunobiology of this arenavirus for vaccine delivery. by using producer cells constitutively synthesizing the viral glycoprotein (gp), it was possible to replace the gene encoding lcmv gp with vaccine antigens to create replication-defective vaccine vectors. these r ...201020139992
cd4+ t cell plasticity-th2 cells join the crowd.in this issue of immunity, hegazy et al. (2010) report that in response to lymphocytic choriomeningitis virus (lcmv) infection, fully differentiated virus-specific th2 cells can be reprogrammed into gata-3(+)t-bet(+) cells capable of producing both interleukin-4 and interferon-gamma.201020152167
an antiviral disulfide compound blocks interaction between arenavirus z protein and cellular promyelocytic leukemia protein.the promyelocytic leukemia protein (pml) forms nuclear bodies (nb) that can be redistributed by virus infection. in particular, lymphocytic choriomeningitis virus (lcmv) influences disruption of pml nb through the interaction of pml with the arenaviral z protein. in a previous report, we have shown that the disulfide compound nsc20625 has antiviral and virucidal properties against arenaviruses, inducing unfolding and oligomerization of z without affecting cellular ring-containing proteins such a ...201020152808
cd8 t cell cross-reactivity networks mediate heterologous immunity in human ebv and murine vaccinia virus infections.in this study, we demonstrate complex networks of cd8 t cell cross-reactivities between influenza a virus and ebv in humans and between lymphocytic choriomeningitis virus and vaccinia virus in mice. we also show directly that cross-reactive t cells mediate protective heterologous immunity in mice. subsets of t cell populations reactive with one epitope cross-reacted with either of several other epitopes encoded by the same or the heterologous virus. human t cells specific to ebv-encoded bmlf1(28 ...201020164414
[laboratory diagnosis of lymphocytic meningitis].lymphocytic meningitis, mainly those with an acute and benign course, are caused by viruses. in our area, the most commonly involved agents are enteroviruses, herpes simplex, varicella zoster and toscana viruses. nucleic acids amplification techniques (naat) are the methods of choice to diagnose viral meningitis from cerebrospinal fluid (csf) samples. they are more rapid and sensitive, and indeed, they are not influenced by the viability of the virus in the clinical specimen as traditional metho ...201020172425
global lymphoid tissue remodeling during a viral infection is orchestrated by a b cell-lymphotoxin-dependent pathway.adaptive immune responses are characterized by substantial restructuring of secondary lymphoid organs. the molecular and cellular factors responsible for virus-induced lymphoid remodeling are not well known to date. here we applied optical projection tomography, a mesoscopic imaging technique, for a global analysis of the entire 3-dimensional structure of mouse peripheral lymph nodes (plns), focusing on b-cell areas and high endothelial venule (hev) networks. structural homeostasis of plns was c ...201020185585
analysis of apoptosis of memory t cells and dendritic cells during the early stages of viral infection or exposure to toll-like receptor agonists.profound type i interferon (ifn-i)-dependent attrition of memory cd8 and cd4 t cells occurs early during many infections. it is dramatic at 2 to 4 days following lymphocytic choriomeningitis virus (lcmv) infection of mice and can be elicited by the ifn-inducing toll receptor agonist poly(i:c). we show that this attrition occurs in many organs, indicating that it is due to t cell loss rather than redistribution. this loss correlated with elevated intracellular staining of t cells ex vivo for acti ...201020200235
a detrimental effect of interleukin-10 on protective pulmonary humoral immunity during primary influenza a virus infection.interleukin-10 (il-10) is an important anti-inflammatory molecule that can cause immunosuppression and long-term pathogen persistence during chronic infection of mice with viruses such as lymphocytic choriomeningitis virus. however, its specific role in immunity to acute viral infections is not fully understood. we found that il-10 plays a detrimental role in host responses to acute influenza a virus since il-10(-/-) mice had improved viral clearance and survival after infection compared to wild ...201020200252
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
loss of dnam-1 contributes to cd8+ t-cell exhaustion in chronic hiv-1 infection.the hallmark of chronic viral infections is a progressive exhaustion of antigen-specific cd8(+) t cells that leads to persisting viral replication. it is generally believed that exhaustion is a consequence of the accumulation of multiple inhibitory receptors on cd8(+) t cells that makes them dysfunctional. here, we show that during human chronic hiv-1 infection, a cd8(+) t-cell positive costimulatory pathway mediated by dnax-activating molecule-1 is also disrupted. thus, dnax-activating molecule ...201020201043
t-cell exhaustion: characteristics, causes and conversion.t-cell exhaustion is characterized by the stepwise and progressive loss of t-cell functions and can culminate in the physical deletion of the responding cells. exhaustion is well-defined during chronic lymphocytic choriomeningitis virus infection and commonly develops under conditions of antigen-persistence, which occur following many chronic infections that are of significant public health concern including hepatitis b virus, hepatitis c virus and human immunodeficiency virus infections, as wel ...201020201977
structural characterization of the z ring-eif4e complex reveals a distinct mode of control for eif4e.the eukaryotic translation initiation factor eif4e, a potent oncogene, is highly regulated. one class of eif4e regulators, including eif4g and the 4e-binding proteins (4e-bps), interact with eif4e using a conserved yxxxxlphi-binding site. the structural basis of this interaction and its regulation are well established. really interesting new gene (ring) domain containing proteins, such as the promyelocytic leukemia protein pml and the arenaviral protein z, represent a second class of eif4e regul ...201020212144
histone acetylation at the single-cell level: a marker of memory cd8+ t cell differentiation and functionality.following stimulation, memory t (t(m)) cells rapidly express many effector functions, a hallmark feature that allows them to provide protective immunity. recent studies suggest that genes involved in this rapid recall response may maintain an open chromatin structure in resting t(m) cells via epigenetic modifications. however, these studies have mostly focused on a few loci, and the techniques used required a large number of cells. we have developed a flow cytometric assay measuring histone modi ...201020308634
cross, but not direct, presentation of cell-associated virus antigens by spleen macrophages is influenced by their differentiation state.the initiation of t-cell immune responses requires professional antigen-presenting cells. emerging data point towards an important role for macrophages (mphi) in the priming of naïve t cells. in this study we analyzed the efficiency and the mechanisms by which mphi derived from spleen (sp-mphi) or bone marrow (bm-mphi) present lymphocytic choriomeningitis virus (lcmv) antigens to epitope-specific t cells. we demonstrate that because of phagosomal maturation, sp-mphi downregulate their ability to ...201019935765
immunization with live attenuated influenza viruses that express altered ns1 proteins results in potent and protective memory cd8+ t-cell responses.the generation of vaccines that induce long-lived protective immunity against influenza virus infections remains a challenging goal. ideally, vaccines should elicit effective humoral and cellular immunity to protect an individual from infection or disease. cross-reactive t- and b-cell responses that are elicited by live virus infections may provide such broad protection. optimal induction of t-cell responses involves the action of type i interferons (ifn-i). influenza virus expressed nonstructur ...201019939929
absence of tapasin alters immunodominance against a lymphocytic choriomeningitis virus polytope.tapasin edits the peptide repertoire presented to cd8(+) t cells by favoring loading of slow off-rate peptides on mhc i molecules. to investigate the role of tapasin on t cell immunodominance we used poxvirus viral vectors expressing a polytope of lymphocytic choriomeningitis virus epitopes with different off-rates. in tapasin-deficient mice, responses to subdominant fast off-rate peptides were clearly favored. this alteration of the cd8(+) t cell hierarchy was a consequence of tapasin editing a ...201019949070
tissue-specific differences in pd-1 and pd-l1 expression during chronic viral infection: implications for cd8 t-cell exhaustion.the pd-1/pd-l pathway plays a major role in regulating t-cell exhaustion during chronic viral infections in animal models, as well as in humans, and blockade of this pathway can revive exhausted cd8(+) t cells. we examined the expression of pd-1 and its ligands, pd-l1 and pd-l2, in multiple tissues during the course of chronic viral infection and determined how the amount of pd-1 expressed, as well as the anatomical location, influenced the function of exhausted cd8 t cells. the amount of pd-1 o ...201019955307
treatment with a sphingosine analog does not alter the outcome of a persistent virus infection.there is no known antiviral drug treatment that routinely terminates persistent virus infections. a recent provocative report indicated that low dosage of the sphingosine analog fty720 caused lymphopenia in mice persistently infected with lymphocytic choriomeningitis virus (lcmv)-clone 13 (cl 13) and induced viral clearance within 30 days post-treatment (premenko-lanier et al., 2008). however, we find that low dosage of fty720 fails to purge lcmv-cl 13 infection and does not induce lymphopenia i ...201019962171
targeting the proteolytic processing of the viral glycoprotein precursor is a promising novel antiviral strategy against arenaviruses.a crucial step in the arenavirus life cycle is the biosynthesis of the viral envelope glycoprotein (gp) responsible for virus attachment and entry. processing of the gp precursor (gpc) by the cellular proprotein convertase site 1 protease (s1p), also known as subtilisin-kexin-isozyme 1 (ski-1), is crucial for cell-to-cell propagation of infection and production of infectious virus. here, we sought to evaluate arenavirus gpc processing by s1p as a target for antiviral therapy using a recently dev ...201019846507
lymphocytic choriomeningitis virus-induced mortality in mice is triggered by edema and brain herniation.although much is known about lymphocytic choriomeningitis virus (lcmv) infection and the subsequent immune response in its natural murine host, some crucial aspects of lcmv-mediated pathogenesis remain undefined, including the underlying basis of the characteristic central nervous system disease that occurs following intracerebral (i.c.) challenge. we show that the classic seizures and paresis that occur following i.c. infection of adult, immunocompetent mice with lcmv are accompanied by anatomi ...201019828618
activation of transgene-specific t cells following lentivirus-mediated gene delivery to mouse lung.integrating lentiviral vectors based on the human immunodeficiency virus type-1 (hiv-1) can transduce quiescent cells, which in lung account for almost 95% of the epithelial cell population. pseudotyping lentiviral vectors with the envelope glycoprotein from the ebola zaire virus, the lymphocytic choriomeningitis virus (lcmv), the mokola virus, and the vesicular stomatitis virus (vsv-g) resulted in transduction of mouse alveolar epithelium, but gene expression in the lung of c57bl/6 and balb/c m ...201019724265
pathological features of heterologous immunity are regulated by the private specificities of the immune repertoire.heterologous immunity associated with cross-reactive t-cell responses is proposed to contribute to variations among individuals in the pathogenesis of human viral infections. in genetically identical mice with similar infection histories, marked variations in the magnitude and specificities of t-cell responses under conditions of heterologous immunity occur and have been linked to the private specificity of t-cell repertoires in individual immune mice. variations in immunopathology in the form o ...201020348239
dendritic cells and stat3 are essential for cd137-induced cd8 t cell activation-induced cell death.agonistic anti-cd137 mabs either positively or negatively regulate t cell function. when administered at the beginning of lymphocytic choriomeningitis virus armstrong infection anti-cd137 induced immunosuppression and t cell deletion, and in the case of influenza infection led to increased mortality. in contrast, 72 h delay in anti-cd137 treatment led to an enhanced virus-specific cd8 t cell response and rapid viral clearance. virus-specific cd8 t cells in anti-cd137-injected mice rapidly upregu ...201020351189
t cells can mediate viral clearance from ependyma but not from brain parenchyma in a major histocompatibility class i- and perforin-independent manner.viral infection of the central nervous system can lead to disability and death. yet the majority of viral infections with central nervous system involvement resolve with only mild clinical manifestations, if any. this is generally attributed to efficient elimination of the infection from the brain coverings, i.e. the meninges, ependyma and chorioplexus, which are the primary targets of haematogeneous viral spread. how the immune system is able to purge these structures from viral infection with ...201020354003
cell-intrinsic defects in the proliferative response of antiviral memory cd8 t cells in aged mice upon secondary infection.although previous studies have demonstrated delayed viral clearance and blunted effector t cell responses in aged mice during infection, memory cd8 t cells and especially secondary responses have received less attention. in this study, we show that modest differences in the number of memory cd8 t cells formed in aged versus young animals were associated with altered memory cd8 t cell differentiation. aged immune mice had increased morbidity and mortality upon secondary viral challenge, suggestin ...201020368274
functional glycosylation of dystroglycan is crucial for thymocyte development in the mouse.alpha-dystroglycan (alpha-dg) is a cell surface receptor providing a molecular link between the extracellular matrix (ecm) and the actin-based cytoskeleton. during its biosynthesis, alpha-dg undergoes specific and unusual o-glycosylation crucial for its function as a high-affinity cellular receptor for ecm proteins.201020369005
granzyme b-induced and caspase 3-dependent cleavage of gelsolin by mouse cytotoxic t cells modifies cytoskeleton dynamics.granule-associated perforin and granzymes (gzms) are key effector molecules of cytotoxic t lymphocytes (tc cells) and natural killer cells and play a critical role in the control of intracellular pathogens and cancer. based on the notion that many gzms, including a, b, c, k, h, and m exhibit cytotoxic activity in vitro, all gzms are believed to serve a similar function in vivo. however, more recent evidence supports the concept that gzms are not unidimensional but, rather, possess non-cytotoxic ...201020395300
microbial induction of vascular pathology in the cns.the central nervous system (cns) is a finely tuned organ that participates in nearly every aspect of our day-to-day function. neurons lie at the core of this functional unit and maintain an active dialogue with one another as well as their fellow cns residents (e.g. astrocytes, oligodendrocytes, microglia). because of this complex dialogue, it is essential that the cns milieu be tightly regulated in order to permit uninterrupted and efficient neural chemistry. this is accomplished in part by ana ...201020401700
viperin is highly induced in neutrophils and macrophages during acute and chronic lymphocytic choriomeningitis virus infection.although most cells are thought to respond to ifns, there is limited information regarding specific cells that respond in vivo. viperin is an ifn-induced antiviral protein and, therefore, is an excellent marker for ifn-responsive cells. in this study, we analyzed viperin expression in vivo during acute lymphocytic choriomeningitis virus armstrong infection, which induces high levels of type i ifns, and in persistently infected lymphocytic choriomeningitis virus carrier mice, which contain low le ...201020410488
gamma(c) deficiency precludes cd8+ t cell memory despite formation of potent t cell effectors.several cytokines (including il-2, il-7, il-15, and il-21) that signal through receptors sharing the common gamma chain (gamma(c)) are critical for the generation and peripheral homeostasis of naive and memory t cells. recently, we demonstrated that effector functions fail to develop in cd4(+) t cells that differentiate in the absence of gamma(c). to assess the role of gamma(c) cytokines in cell-fate decisions that condition effector versus memory cd8(+) t cell generation, we compared the respon ...201020439728
absence of mouse 2b4 promotes nk cell-mediated killing of activated cd8+ t cells, leading to prolonged viral persistence and altered pathogenesis.persistent viral infections are often associated with inefficient t cell responses and sustained high-level expression of inhibitory receptors, such as the nk cell receptor 2b4 (also known as cd244), on virus-specific t cells. however, the role of 2b4 in t cell dysfunction is undefined, and it is unknown whether nk cells contribute to regulation of these processes. we show here that persistent lymphocytic choriomeningitis virus (lcmv) infection of mice lacking 2b4 resulted in diminished lcmv-spe ...201020440077
essential role of the wnt pathway effector tcf-1 for the establishment of functional cd8 t cell memory.immune protection from intracellular pathogens depends on the generation of terminally differentiated effector and of multipotent memory precursor cd8 t cells, which rapidly regenerate effector and memory cells during recurrent infection. the identification of factors and pathways involved in cd8 t cell differentiation is of obvious importance to improve vaccination strategies. here, we show that mice lacking t cell factor 1 (tcf-1), a nuclear effector of the canonical wingless/integration 1 (wn ...201020457902
host mechanisms in viral hepatitis.hepatitis, a common human disease, may be followed by severe liver injury, eventually leading to fatty liver, liver fibrosis and hepatocellular carcinoma. cd8 t cells are a double-edged sword in the response to infection with the hepatitis virus. on one hand, rapid activation of cd8 t cells is critically important for the elimination of the virus. on the other hand, in persistent viral infection, the activation of cd8 t cells substantially contributes to liver injury. the clinical course of hepa ...201020460887
distinct roles for il-2 and il-15 in the differentiation and survival of cd8+ effector and memory t cells.il-2 provides a memory differentiation signal to cd8+ t cells during the primary response that impacts the ability of the subsequent memory pool to mount a successful recall response. in this study, we find that although primary effector ctl development is modestly decreased in the absence of il-2, the persistence of short-term and long-term effector memory cd8+ t cells on pathogen clearance is greatly diminished. furthermore, secondary challenge of cd8+ memory t cells lacking the high-avidity i ...201020483725
essential role for tlr9 in prime but not prime-boost plasmid dna vaccination to activate dendritic cells and protect from lethal viral infection.one of the requirements for efficient vaccination against infection is to achieve the best combination of an adequate adjuvant with the antigenic information to deliver. although plasmid dna is a promising tool bearing the unique potential to activate humoral and cellular immunity, an actual challenge is to increase plasmid immunogenicity in human vaccination protocols in which efficacy has proven rather limited. previous work showed that the bacterial dna backbone of the plasmid has potent adju ...201020483769
human infection with lymphocytic choriomeningitis virus. 201020507777
coverage of related pathogenic species by multivalent and cross-protective vaccine design: arenaviruses as a model system.the arenaviruses are a family of negative-sense rna viruses that cause severe human disease ranging from aseptic meningitis to hemorrhagic fever syndromes. there are currently no fda-approved vaccines for the prevention of arenavirus disease, and therapeutic treatment is limited to the use of ribavirin and/or immune plasma for a subset of the pathogenic arenaviruses. the considerable genetic variability observed among the seven arenaviruses that are pathogenic for humans illustrates one of the m ...201020508245
the outcome of cross-priming during virus infection is not directly linked to the ability of the antigen to be cross-presented.the initiation of cd8(+) t cell (ctl) immune responses can occur via cross-priming. recent data suggested a relationship between cross-presentation and immunodominance of epitope-specific t cells. to test this association, we evaluated the efficacy of cross-presentation for several virus epitopes in vitro and examined if this can be extrapolated in vivo. employing lymphocytic choriomeningitis virus (lcmv), we demonstrate that the cross-presentation and cross-priming of lcmv antigens were dominat ...201020518030
serine protease inhibitor 6 protects inkt cells from self-inflicted damage.the role played by apoptosis in the homeostasis of effector cells of the innate immune system is unclear. serine protease inhibitor 6 (spi6) is an inhibitor of granzyme b (grb) that protects cytotoxic t lymphocytes of the adaptive immune system from apoptosis. to determine whether spi6 also protects cells of the innate immune system from self-inflicted damage we have examined invariant nkt (inkt) cells. spi6-deficient inkt cells harbored increased levels of grb after tcr stimulation with the pbs ...201020543105
pd-l1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating t cell responses during chronic infection in mice.the inhibitory receptor programmed death 1 (pd-1) is upregulated on antigen-specific cd8+ t cells during persistent viral infections. interaction with pd-1 ligand 1 (pd-l1) contributes to functional exhaustion of responding t cells and may limit immunopathology during infection. pd-l1 is expressed on both hematopoietic and nonhematopoietic cells in tissues. however, the exact roles of pd-l1 on hematopoietic versus nonhematopoietic cells in modulating immune responses are unclear. here we used bo ...201020551512
is il-7 from dendritic cells essential for the homeostasis of cd4+ t cells? 201020562832
minimal effect of cd103 expression on the control of a chronic antiviral immune response.impaired antiviral cd8 and cd4 t-cell responses are often associated with chronic viral infections. cell-intrinsic as well as cell-extrinsic mechanisms are thought to dampen such responses, for example programmed death 1 receptor (pd-1) expression on t cells, and interleukin (il)-10 production primarily by dendritic cells (dcs), have been shown to support viral persistence by suppressing immune responses. here we demonstrate that cd103, an alpha e integrin necessary for t-cell homing and retenti ...201020565292
the alternative nf-kappab signalling pathway is a prerequisite for an appropriate immune response against lymphocytic choriomeningitis virus infection.two major nuclear factor-kappab (nf-kappab) signalling pathways are involved in the regulation of the immune response. while the classical nf-kappab pathway is responsible for regulation of genes encoding components of the innate immune response, the alternative nf-kappab signalling pathway mediates processes of the adaptive immune system. to evaluate the role of the nf-kappab signalling pathways in the control of viral infection, we have used lymphocytic choriomeningitis virus (lcmv) infection ...201020565293
tissue macrophages suppress viral replication and prevent severe immunopathology in an interferon-i-dependent manner in mice.the innate immune response plays an essential role in the prevention of early viral dissemination. we used the lymphocytic choriomeningitis virus model system to analyze the role of tissue macrophages/kupffer cells in this process. our findings demonstrated that kupffer cells are essential for the efficient capture of infectious virus and for preventing viral replication. the latter process involved activation of kupffer cells by interferon (ifn)-i and prevented viral spread to neighboring hepat ...201020578253
persistence of viral infection despite similar killing efficacy of antiviral cd8(+) t cells during acute and chronic phases of infection.why some viruses establish chronic infections while others do not is poorly understood. one possibility is that the host's immune response is impaired during chronic infections and is unable to clear the virus from the host. in this report, we use a recently proposed framework to estimate the per capita killing efficacy of cd8(+) t cells, specific for the polyoma virus (pyv), which establishes a chronic infection in mice. surprisingly, the estimated per cell killing efficacy of pyv-specific effe ...201020580390
innate and adaptive immune control of genetically engineered live-attenuated arenavirus vaccine prototypes.arenaviruses such as lassa virus (lasv) cause significant morbidity and mortality in endemic areas. using a glycoprotein (gp) exchange strategy, we have recently developed live-attenuated arenavirus vaccine prototypes (rlcmv/vsvg) based on lymphocytic choriomeningitis virus (lcmv), a close relative of lasv. rlcmv/vsvg induced long-term cd8(+) t cell immunity against wild-type virus challenge and exhibited a stably attenuated phenotype in vivo. here we elucidated the innate and adaptive immune re ...201020584765
role of pkr and type i ifns in viral control during primary and secondary infection.type i interferons (ifns) are known to mediate viral control, and also promote survival and expansion of virus-specific cd8+ t cells. however, it is unclear whether signaling cascades involved in eliciting these diverse cellular effects are also distinct. one of the best-characterized anti-viral signaling mechanisms of type i ifns is mediated by the ifn-inducible dsrna activated protein kinase, pkr. here, we have investigated the role of pkr and type i ifns in regulating viral clearance and cd8+ ...201020585572
high diversity and ancient common ancestry of lymphocytic choriomeningitis virus.lymphocytic choriomeningitis virus (lcmv) is the prototype of the family arenaviridae. lcmv can be associated with severe disease in humans, and its global distribution reflects the broad dispersion of the primary rodent reservoir, the house mouse (mus musculus). recent interest in the natural history of the virus has been stimulated by increasing recognition of lcmv infections during pregnancy, and in clusters of lcmv-associated fatal illness among tissue transplant recipients. despite its publ ...201020587180
induction and inhibition of type i interferon responses by distinct components of lymphocytic choriomeningitis virus.type i interferons (ifns) play a critical role in the host defense against viruses. lymphocytic choriomeningitis virus (lcmv) infection induces robust type i ifn production in its natural host, the mouse. however, the mechanisms underlying the induction of type i ifns in response to lcmv infection have not yet been clearly defined. in the present study, we demonstrate that irf7 is required for both the early phase (day 1 postinfection) and the late phase (day 2 postinfection) of the type i ifn r ...201020592086
the role of cd80/cd86 in generation and maintenance of functional virus-specific cd8+ t cells in mice infected with lymphocytic choriomeningitis virus.lymphocytic choriomeningitis virus (lcmv)-specific cd8(+) t cell responses are considered to be independent of cd28-b7 costimulation. however, the lcmv-specific response has never been evaluated in b7.1/b7.2(-/-) mice. for this reason, we decided to study the t cell response in b7.1/b7.2(-/-) mice infected with two different strains of lcmv, one (traub strain) typically causing low-grade chronic infection, and another (armstrong clone 53b) displaying very limited capacity for establishing chroni ...201020601595
discovery of a novel tlr2 signaling inhibitor with anti-viral activity.blockade of toll-like receptor (tlr)-mediated inflammatory responses represents a new approach in the development of anti-inflammation therapeutics. in the present study, we have screened for tlr2-mediated inflammation inhibitors from small molecule compound libraries using a sensitive cell line stably expressing tlr2, cd14, and an nf-kappab-driven-luciferase reporter gene. lymphocytic choriomeningitis virus (lcmv) was used as a virus model. this arenavirus activates a tlr2/cd14-dependent nf-kap ...201020603154
androgens suppress antigen-specific t cell responses and ifn-γ production during intracranial lcmv infection.intracranial (i.c.) lymphocytic choriomeningitis virus (lcmv) infection of mice results in t cell-driven anorexia and weight loss, which is diminished in males compared to females. we investigated sex-specific effects on antigen-presenting cells (apcs) and t cells after i.c. lcmv infection. numbers of lcmv-specific t cells, apc activation, and levels of inflammatory cytokines and chemokines in csf were decreased in males compared to females. orchidectomy enhanced these immune parameters in males ...201020619904
qualitatively different memory cd8+ t cells are generated after lymphocytic choriomeningitis virus and influenza virus infections.viral infections often induce robust t cell responses that are long-lived and protective. however, it is unclear to what degree systemic versus mucosal infection influences the generation of effector and memory t cells. in this study, we characterized memory cd8(+) t cells generated after respiratory influenza virus infection and compared the phenotypic and functional qualities of these cells with memory t cells generated after systemic infection with lymphocytic choriomeningitis virus (lcmv). u ...201020639484
stat5 is critical to maintain effector cd8+ t cell responses.during an immune response, most effector t cells die, whereas some are maintained and become memory t cells. factors controlling the survival of effector cd4(+) and cd8(+) t cells remain unclear. in this study, we assessed the role of il-7, il-15, and their common signal transducer, stat5, in maintaining effector cd4(+) and cd8(+) t cell responses. following viral infection, il-15 was required to maintain a subpopulation of effector cd8(+) t cells expressing high levels of killer cell lectin-lik ...201020644163
the effects of preexisting immunity to influenza on responses to influenza vectors in mice.the use of viral vectors as vaccine candidates has shown promise against a number of pathogens. however, preexisting immunity to these vectors is a concern that must be addressed when deciding which viruses are suitable for use. a number of properties, including the existence of antigenically distinct subtypes, make influenza viruses attractive candidates for use as viral vectors. here, we evaluate the ability of influenza viral vectors containing inserts of foreign pathogens to elicit antibody ...201020656032
allografts stimulate cross-reactive virus-specific memory cd8 t cells with private specificity.viral infections have been associated with the rejection of transplanted allografts in humans and mice, and the induction of tolerance to allogeneic tissues in mice is abrogated by an ongoing viral infection and inhibited in virus-immune mice. one proposed mechanism for this 'heterologous immunity' is the induction of alloreactive t cell responses that cross-react with virus-derived antigens. these cross-reactive cd8 t cells are generated during acute viral infection and survive into memory, but ...201020659086
a multivalent vaccination strategy for the prevention of old world arenavirus infection in humans.arenaviruses cause severe human disease ranging from aseptic meningitis following lymphocytic choriomeningitis virus (lcmv) infection to hemorrhagic fever syndromes following infection with guanarito virus (gtov), junin virus (junv), lassa virus (lasv), machupo virus (macv), sabia virus (sabv), or whitewater arroyo virus (wwav). cellular immunity, chiefly the cd8(+) t-cell response, plays a critical role in providing protective immunity following infection with the old world arenaviruses lasv an ...201020668086
cooperation of tim-3 and pd-1 in cd8 t-cell exhaustion during chronic viral infection.inhibitory receptors play a crucial role in regulating cd8 t-cell function during chronic viral infection. t-cell ig- and mucin-domain-containing molecule-3 (tim-3) is well known to negatively regulate t-cell responses, but its role in cd8 t-cell exhaustion during chronic infection in vivo remains unclear. in this study, we document coregulation of cd8 t cell exhaustion by tim-3 and pd-1 during chronic lymphocytic choriomeningitis virus infection. whereas tim-3 was only transiently expressed by ...201020679213
fidelity of pathogen-specific cd4+ t cells to the th1 lineage is controlled by exogenous cytokines, interferon-gamma expression, and pathogen lifestyle.the degree of lineage stability achieved by pathogen-specific cd4(+) t cells in vivo, and how this impacts host defense against infection, remains unclear. we demonstrate that in response to th1-polarizing intracellular bacterial or viral pathogens, only 80%-90% of responding polyclonal t cells become indelibly committed to this lineage. th1 commitment was nearly invariant in cells that proliferated extensively, but perturbations to the extrinsic cytokine milieu or the pathogen's ability to ente ...201020709293
both systemic and mucosal lcmv immunization generate robust viral-specific igg in mucosal secretions, but elicit poor lcmv-specific iga.immunoglobulins in secretions play a critical role in protection at mucosal surfaces. we examined the generation of viral-specific igg and iga in plasma and mucosal secretions of mice following systemic or mucosal immunization with lymphocytic choriomeningitis virus (lcmv), a widely used experimental model of viral infection. while there are early differences in humoral responses depending on the route of viral entry, we show that both routes generate comparably robust viral-specific igg in plas ...201020712482
pronounced virus-dependent activation drives exhaustion but sustains ifn-γ transcript levels.during many chronic infections, the responding cd8 t cells become exhausted as they progressively lose their ability to elaborate key effector functions. unlike prototypic memory cd8 cells, which rapidly synthesize ifn-gamma following activation, severely exhausted t cells fail to produce this effector molecule. nevertheless, the ontogeny of exhausted cd8 t cells, as well as the underlying mechanisms that account for their functional inactivation, remains ill defined. we have used cytokine repor ...201020720198
attenuation of the cytotoxic t lymphocyte response to lymphocytic choriomeningitis virus in mice subjected to chronic social stress.chronic stress is suspected to increase the susceptibility to infections but experimental evidence from physiological stress models is scarce. we examined the effects of chronic social stress on virus-specific ctl responses in mice after infection with lymphocytic choriomeningitis virus (lcmv). mice subjected to social stress on six consecutive days prior to infection showed a significant reduction of ifn-γ producing t(cd8+) splenocytes and markedly lowered plasma concentrations of ifn-γ. in con ...201020974245
pseudotype-dependent lentiviral transduction of astrocytes or neurons in the rat substantia nigra.gene transfer to the central nervous system provides powerful methodology for the study of gene function and gene-environment interactions in vivo, in addition to a vehicle for the delivery of therapeutic transgenes for gene therapy. the aim of the present study was to determine patterns of tropism exhibited by pseudotyped lentiviral vectors in the rat substantia nigra, in order to evaluate their utility for gene transfer in experimental models of parkinson's disease. isogenic lentiviral vector ...201021056560
glycosylation modulates arenavirus glycoprotein expression and function.the glycoprotein of lymphocytic choriomeningitis virus (lcmv) contains nine potential n-linked glycosylation sites. we investigated the function of these n-glycosylations by using alanine-scanning mutagenesis. all the available sites were occupied on gp1 and two of three on gp2. n-linked glycan mutations at positions 87 and 97 on gp1 resulted in reduction of expression and absence of cleavage and were necessary for downstream functions, as confirmed by the loss of gp-mediated fusion activity wit ...201021056893
antiviral activity of a small-molecule inhibitor of arenavirus glycoprotein processing by the cellular site 1 protease.arenaviruses merit interest as clinically important human pathogens and include several causative agents, chiefly lassa virus (lasv), of hemorrhagic fever disease in humans. there are no licensed lasv vaccines, and current antiarenavirus therapy is limited to the use of ribavirin, which is only partially effective and is associated with significant side effects. the arenavirus glycoprotein (gp) precursor gpc is processed by the cellular site 1 protease (s1p) to generate the peripheral virion att ...201021068251
immunoproteasomes are essential for survival and expansion of t cells in virus-infected mice.immunoproteasomes containing the ifn-inducible subunits β1i (lmp2), β2i (mecl-1) and β5i (lmp7) alter proteasomal cleavage preference and optimize the generation of peptide ligands of mhc class i molecules. here, we report on an unexpected new function of immunoproteasome subunits for the survival and expansion of cd4(+) and cd8(+) t cells during viral infection of mice. the effect of immunoproteasome subunit deficiency on t-cell survival upon adoptive transfer was most prominent for the lack of ...201021072883
t cells acquire cell surface determinants of apc via in vivo trogocytosis during viral infections.trogocytosis describes the transfer of surface determinants between immune cells and has been implicated in immune regulation. most findings are based on in vitro studies since in vivo trogocytosis of immune cells is difficult to detect under physiological conditions. we used low frequencies of memory p14 t cells to demonstrate that t cells perform trogocytosis in vivo if in contact with apc pulsed with gp33-peptide or expressing the antigen endogenously. furthermore, in vivo trogocytosis of t c ...201021080375
viral replicative capacity is the primary determinant of lymphocytic choriomeningitis virus persistence and immunosuppression.the clone 13 (cl13) strain of lymphocytic choriomeningitis virus is widely studied as a model of chronic systemic viral infection. here, we used reverse genetic techniques to identify the molecular basis of cl13 persistence and immunosuppression, the characteristics differentiating it from the closely related armstrong strain. we found that a single-point mutation in the cl13 polymerase was necessary and partially sufficient for viral persistence and immunosuppression. a glycoprotein mutation kn ...201021098292
inhibition of enveloped virus infection of cultured cells by valproic acid.valproic acid (vpa) is a short-chain fatty acid commonly used for treatment of neurological disorders. as vpa can interfere with cellular lipid metabolism, its effect on the infection of cultured cells by viruses of seven viral families relevant to human and animal health, including eight enveloped and four nonenveloped viruses, was analyzed. vpa drastically inhibited multiplication of all the enveloped viruses tested, including the zoonotic lymphocytic choriomeningitis virus and west nile virus ...201021106740
role of the host cell's unfolded protein response in arenavirus infection.arenaviruses are enveloped rna viruses with a nonlytic life cycle that cause acute and persistent infections. here, we investigated the role of the host cell's unfolded protein response (upr) in infection of the prototypic arenavirus lymphocytic choriomeningitis virus (lcmv). in mammalian cells, the endoplasmic reticulum (er) chaperone protein grp78/bip functions as the principal sensor for the induction of the upr and interacts with three mediators: kinase/endonuclease inositol-requiring protei ...201021106748
immunoproteasomes are essential for survival and expansion of t cells in virus-infected mice.immunoproteasomes containing the ifn-inducible subunits β1i (lmp2), β2i (mecl-1) and β5i (lmp7) alter proteasomal cleavage preference and optimize the generation of peptide ligands of mhc class i molecules. here, we report on an unexpected new function of immunoproteasome subunits for the survival and expansion of cd4(+) and cd8(+) t cells during viral infection of mice. the effect of immunoproteasome subunit deficiency on t-cell survival upon adoptive transfer was most prominent for the lack of ...201021108466
t-705 (favipiravir) inhibition of arenavirus replication in cell culture.a number of new world arenaviruses (junín [junv], machupo [macv], and guanarito [gtov] viruses) can cause human disease ranging from mild febrile illness to a severe and often fatal hemorrhagic fever syndrome. these highly pathogenic viruses and the old world lassa fever virus pose a significant threat to public health and national security. the only licensed antiviral agent with activity against these viruses, ribavirin, has had mixed success in treating severe arenaviral disease and is associa ...201021115797
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