Publications
| Title | Abstract | Year(sorted ascending) Filter | PMID Filter |
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| hematopoietic and nonhematopoietic cells promote type i interferon- and tlr7-dependent monocytosis during low-dose lcmv infection. | release of inflammatory monocytes from the bone marrow (bm) into the blood is an important physiological response to infection, but the mechanisms regulating this phenomenon during viral infection are not completely defined. here, we show that low-dose infection with lymphocytic choriomeningitis virus (lcmv) caused rapid, transient inflammatory monocytosis that required type i interferon (ifn) and toll-like receptor (tlr) 7 signaling. type i ifn and tlr7 signals were critical for induction of if ... | 2015 | 26289159 |
| virus-induced type i interferon deteriorates control of systemic pseudomonas aeruginosa infection. | type i interferon (ifn-i) predisposes to bacterial superinfections, an important problem during viral infection or treatment with interferon-alpha (ifn-α). ifn-i-induced neutropenia is one reason for the impaired bacterial control; however there is evidence that more frequent bacterial infections during ifn-α-treatment occur independently of neutropenia. | 2015 | 26279441 |
| increased immune response variability during simultaneous viral coinfection leads to unpredictability in cd8 t cell immunity and pathogenesis. | t cell memory is usually studied in the context of infection with a single pathogen in naive mice, but how memory develops during a coinfection with two pathogens, as frequently occurs in nature or after vaccination, is far less studied. here, we questioned how the competition between immune responses to two viruses in the same naive host would influence the development of cd8 t cell memory and subsequent disease outcome upon challenge. using two different models of coinfection, including the we ... | 2015 | 26269191 |
| the viral context instructs the redundancy of costimulatory pathways in driving cd8(+) t cell expansion. | signals delivered by costimulatory molecules are implicated in driving t cell expansion. the requirements for these signals, however, vary from dispensable to essential in different infections. we examined the underlying mechanisms of this differential t cell costimulation dependence and found that the viral context determined the dependence on cd28/b7-mediated costimulation for expansion of naive and memory cd8(+) t cells, indicating that the requirement for costimulatory signals is not imprint ... | 2015 | 26263500 |
| il-33 promotes innate ifn-γ production and modulates dendritic cell response in lcmv-induced hepatitis in mice. | recent studies have revealed il-33 as a key factor in promoting antiviral t-cell responses. however, it is less clear as to how il-33 regulates innate immunity. in this study, we infected wild-type (wt) and il-33(-/-) mice with lymphocytic choriomeningitis virus and demonstrated an essential role of infection-induced il-33 expression for robust innate ifn-γ production in the liver. we first show that il-33 deficiency resulted in a marked reduction in the number of ifn-γ(+) γδ t and nk cells, but ... | 2015 | 26249267 |
| id3 controls cell death of 2b4+ virus-specific cd8+ t cells in chronic viral infection. | sustained ag persistence in chronic infection results in a deregulated cd8(+) t cell response that is characterized by t cell exhaustion and cell death of ag-specific cd8(+) t cells. yet, the underlying transcriptional mechanisms regulating cd8(+) t cell exhaustion and cell death are poorly defined. using the experimental mouse model of lymphocytic choriomeningitis virus infection, we demonstrate that the transcriptional regulator id3 controls cell death of virus-specific cd8(+) t cells in chron ... | 2015 | 26232435 |
| production of il-10 by cd4(+) regulatory t cells during the resolution of infection promotes the maturation of memory cd8(+) t cells. | memory cd8(+) t cells are critical for host defense upon reexposure to intracellular pathogens. we found that interleukin 10 (il-10) derived from cd4(+) regulatory t cells (treg cells) was necessary for the maturation of memory cd8(+) t cells following acute infection with lymphocytic choriomeningitis virus (lcmv). treg cell-derived il-10 was most important during the resolution phase, calming inflammation and the activation state of dendritic cells. adoptive transfer of il-10-sufficient treg ce ... | 2015 | 26147684 |
| a jekyll and hyde profile: type 1 interferon signaling plays a prominent role in the initiation and maintenance of a persistent virus infection. | the hallmarks of persistent viral infections are exhaustion of virus-specific t cells, elevated production of interleukin 10 (il-10) and programmed death-1 (pd-1) the dominant negative regulators of the immune system and disruption of secondary lymphoid tissues. within the first 12-24 hours after mice are infected with lymphocytic choriomeningitis virus (lcmv) clone 13, which is used as a model of persistent virus infection, we note generation of high titers of type 1 interferon. blockade of typ ... | 2015 | 26116728 |
| cd4 t cell depletion substantially augments the rescue potential of pd-l1 blockade for deeply exhausted cd8 t cells. | in various models of chronic infections and cancers, blockade of the inhibitory programmed cell death-1 (pd-1) pathway has been shown to be promising at restoring immune function. however, there is not a complete understanding of the factors that influence responsiveness to programmed death-ligand 1 (pd-l1) blockade. in particular, it is currently unclear whether the efficacy of pd-l1 blockade is dependent on the stage of disease. in a model of chronic lymphocytic choriomeningitis virus infectio ... | 2015 | 26116499 |
| c-iap ubiquitin protein ligase activity is required for 4-1bb signaling and cd8(+) memory t-cell survival. | cellular inhibitor of apoptosis proteins (c-iap) 1 and 2 are widely expressed ubiquitin protein ligases that regulate a variety of cellular functions, including the sensitivity of t cells to costimulation. 4-1bb is a tnf receptor family member that signals via a complex that includes traf family members and the c-iaps to upregulate nf-κb and erk, and has been implicated in memory t-cell survival. here, we show that effector and memory t cells from mice expressing a dominant negative e3-inactive ... | 2015 | 26096449 |
| cell-intrinsic gp130 signaling on cd4+ t cells shapes long-lasting antiviral immunity. | the il-6 cytokine family utilizes the common signal transduction molecule gp130, which can mediate a diverse range of outcomes. to clarify the role of gp130 signaling in vivo during acute viral infection, we infected cd4-cre il6st(fl/fl) mice, in which gp130 is conditionally ablated in t cells, with acute lymphocytic choriomeningitis virus. we found that by day 12, but not at day 8, after infection the number of virus-specific cd4(+) t cells was reduced in the absence of gp130, and this was sust ... | 2015 | 26085685 |
| genetic absence of pd-1 promotes accumulation of terminally differentiated exhausted cd8+ t cells. | programmed death-1 (pd-1) has received considerable attention as a key regulator of cd8(+) t cell exhaustion during chronic infection and cancer because blockade of this pathway partially reverses t cell dysfunction. although the pd-1 pathway is critical in regulating established "exhausted" cd8(+) t cells (tex cells), it is unclear whether pd-1 directly causes t cell exhaustion. we show that pd-1 is not required for the induction of exhaustion in mice with chronic lymphocytic choriomeningitis v ... | 2015 | 26034050 |
| cytokine-mediated activation of nk cells during viral infection. | natural killer (nk) cells provide a first line of defense against infection via the production of antiviral cytokines and direct lysis of target cells. cytokines such as interleukin 12 (il-12) and il-18 are critical regulators of nk cell activation, but much remains to be learned about how cytokines interact to regulate nk cell function. here, we have examined cytokine-mediated activation of nk cells during infection with two natural mouse pathogens, lymphocytic choriomeningitis virus (lcmv) and ... | 2015 | 25995253 |
| polymicrobial sepsis increases susceptibility to chronic viral infection and exacerbates cd8+ t cell exhaustion. | patients who survive sepsis display suppressed immune functions, often manifested as an increased susceptibility to secondary infections. recently, using a cecal-ligation and puncture (clp) model of sepsis, we showed that sepsis induces substantial and long-lasting changes in the available naive cd8(+) t cell repertoire affecting the capacity of the host to respond to newly encountered acute infections. however, the extent to which sepsis changes the host susceptibility to chronic infection and ... | 2015 | 25980007 |
| strand-specific quantitative reverse transcription-polymerase chain reaction assay for measurement of arenavirus genomic and antigenomic rnas. | arenaviruses are bi-segmented, single-stranded rna viruses that cause significant human disease. the manner in which they regulate the replication of their genome is not well-understood. this is partly due to the absence of a highly sensitive assay to measure individual species of arenavirus replicative rnas. to overcome this obstacle, we designed a quantitative reverse transcription (rt)-pcr assay for selective quantitation of each of the lymphocytic choriomeningitis virus (lcmv) genomic or ant ... | 2015 | 25978311 |
| arenavirus genome rearrangement for the development of live attenuated vaccines. | several members of the arenaviridae family cause hemorrhagic fever disease in humans and pose serious public health problems in their geographic regions of endemicity as well as a credible biodefense threat. to date, there have been no fda-approved arenavirus vaccines, and current antiarenaviral therapy is limited to an off-label use of ribavirin that is only partially effective. arenaviruses are enveloped viruses with a bisegmented negative-stranded rna genome. each genome segment uses an ambis ... | 2015 | 25972555 |
| cutting edge: t follicular helper cell differentiation is defective in the absence of bcl6 btb repressor domain function. | t follicular helper (tfh) cells are essential for germinal centers (gcs) and most long-term humoral immunity. differentiation of tfh cells depends on the transcriptional repressor b cell cll/lymphoma 6 (bcl6). bcl6 mediates gene repression via the recruitment of corepressors. currently, it is unknown how bcl6 recruits corepressors to regulate gene expression of tfh cells. in this article, we demonstrate, using a mutant form of bcl6 with two btb (bric-a-brac, tramtrack, broad-complex) mutations t ... | 2015 | 25957170 |
| pd-1 upregulated on regulatory t cells during chronic virus infection enhances the suppression of cd8+ t cell immune response via the interaction with pd-l1 expressed on cd8+ t cells. | regulatory t (treg) cells act as terminators of t cell immuniy during acute phase of viral infection; however, their role and suppressive mechanism in chronic viral infection are not completely understood. in this study, we compared the phenotype and function of treg cells during acute or chronic infection with lymphocytic choriomeningitis virus. chronic infection, unlike acute infection, led to a large expansion of treg cells and their upregulation of programmed death-1 (pd-1). treg cells from ... | 2015 | 25934860 |
| estimating the in vivo killing efficacy of cytotoxic t lymphocytes across different peptide-mhc complex densities. | cytotoxic t lymphocytes (ctls) are important agents in the control of intracellular pathogens, which specifically recognize and kill infected cells. recently developed experimental methods allow the estimation of the ctl's efficacy in detecting and clearing infected host cells. one method, the in vivo killing assay, utilizes the adoptive transfer of antigen displaying target cells into the bloodstream of mice. surprisingly, killing efficacies measured by this method are often much higher than es ... | 2015 | 25933039 |
| single nucleoprotein residue modulates arenavirus replication complex formation. | the arenaviridae are enveloped, negative-sense rna viruses with several family members that cause hemorrhagic fevers. this work provides immunofluorescence evidence that, unlike those of new world arenaviruses, the replication and transcription complexes (rtc) of lymphocytic choriomeningitis virus (lcmv) colocalize with eukaryotic initiation factor 4e (eif4e) and that eif4e may participate in the translation of lcmv mrna. additionally, we identify two residues in the lcmv nucleoprotein (np) that ... | 2015 | 25922393 |
| t cell metabolism. the protein lem promotes cd8⁺ t cell immunity through effects on mitochondrial respiration. | protective cd8(+) t cell-mediated immunity requires a massive expansion in cell number and the development of long-lived memory cells. using forward genetics in mice, we identified an orphan protein named lymphocyte expansion molecule (lem) that promoted antigen-dependent cd8(+) t cell proliferation, effector function, and memory cell generation in response to infection with lymphocytic choriomeningitis virus. generation of lem-deficient mice confirmed these results. through interaction with cr6 ... | 2015 | 25883318 |
| evaluation of non-reciprocal heterologous immunity between unrelated viruses. | heterologous immunity refers to the phenomenon whereby a history of an immune response against one pathogen can provide a level of immunity to a second unrelated pathogen. previous investigations have shown that heterologous immunity is not necessarily reciprocal, such as in the case of vaccinia virus (vacv). replication of vacv is reduced in mice immune to a variety of pathogens, while vacv fails to induce immunity to several of the same pathogens, including lymphocytic choriomeningitis virus ( ... | 2015 | 25838115 |
| lymphocytic choriomeningitis virus differentially affects the virus-induced type i interferon response and mitochondrial apoptosis mediated by rig-i/mavs. | arenaviruses are important emerging human pathogens maintained by noncytolytic persistent infection in their rodent reservoir hosts. despite high levels of viral replication, persistently infected carrier hosts show only mildly elevated levels of type i interferon (ifn-i). accordingly, the arenavirus nucleoprotein (np) has been identified as a potent ifn-i antagonist capable of blocking activation of interferon regulatory factor 3 (irf3) via the retinoic acid inducible gene (rig)-i/mitochondrial ... | 2015 | 25833049 |
| antiviral effect of interferon lambda against lymphocytic choriomeningitis virus. | lambda interferons inhibit replication of many viruses, but their role in the inhibition of lymphocytic choriomeningitis virus (lcmv) infection remains unclear. in this study, we examined the antiviral effects of interferon (ifn)-λ2 and ifn-λ3 against lcmv in a549 cells. we found that ifn-λ2 is a more potent inhibitor of lcmv strain mx compared with ifn-λ3, whereas both cytokines have similar antiviral effects against an immunosuppressive variant of lcmv, clone-13. we also demonstrated that the ... | 2015 | 25830339 |
| t-bet- and stat4-dependent il-33 receptor expression directly promotes antiviral th1 cell responses. | during infection, the release of damage-associated molecular patterns, so-called "alarmins," orchestrates the immune response. the alarmin il-33 plays a role in a wide range of pathologies. upon release, il-33 signals through its receptor st2, which reportedly is expressed only on cd4(+) t cells of the th2 and regulatory subsets. here we show that th1 effector cells also express st2 upon differentiation in vitro and in vivo during lymphocytic choriomeningitis virus (lcmv) infection. the expressi ... | 2015 | 25829541 |
| a ceramide analogue stimulates dendritic cells to promote t cell responses upon virus infections. | the ceramide family of lipids plays important roles in both cell structure and signaling in a diverse array of cell types, including immune cells. however, very little is known regarding how ceramide affects the activation of dendritic cells (dcs) in response to viral infection. in this study, we demonstrate that a synthetic ceramide analog (c8) stimulates dcs to increase the expansion of virus-specific t cells upon virus infection. exogenously supplied c8 ceramide elevated the expression of dc ... | 2015 | 25810392 |
| analgesia in mice with experimental meningitis reduces pain without altering immune parameters. | intracranial lymphocytic choriomeningitis virus (lcmv) infection is a widely used animal model to study virus-induced cytotoxic t cell (ctl) mediated meningitis and immunopathology. nevertheless, this model causes severe pain and distress in mice, especially at later stages of the disease. therefore, new treatment regimens to improve animal welfare have to be developed. in this study, we subcutaneously implanted alzet® osmotic pumps continuously releasing buprenorphine to reduce pain in mice wit ... | 2015 | 25800953 |
| functional restoration of exhausted cd4(+) and cd8(+) t cells in chronic viral infection by vinegar-processed flos of daphne genkwa. | t-cell exhaustion has become an important issue in chronic infection because exhausted antigen-specific t cells show impaired abilities to eradicate persistently infected pathogens and produce effector cytokines, such as ifn-γ and tnf-α. thus, strategies to either restore endogenous exhausted t cell responses or provide functional t cells are needed for therapeutics of chronic infection. despite promising developments using antibodies and cell immunotherapy, there have been no reported attempts ... | 2015 | 25744061 |
| suppression of fcγ-receptor-mediated antibody effector function during persistent viral infection. | understanding how viruses subvert host immunity and persist is essential for developing strategies to eliminate infection. t cell exhaustion during chronic viral infection is well described, but effects on antibody-mediated effector activity are unclear. herein, we show that increased amounts of immune complexes generated in mice persistently infected with lymphocytic choriomeningitis virus (lcmv) suppressed multiple fcγ-receptor (fcγr) functions. the high amounts of immune complexes suppressed ... | 2015 | 25680277 |
| antibody effector functions mediated by fcγ-receptors are compromised during persistent viral infection. | t cell dysfunction is well documented during chronic viral infections but little is known about functional abnormalities in humoral immunity. here we report that mice persistently infected with lymphocytic choriomeningitis virus (lcmv) exhibit a severe defect in fcγ-receptor (fcγr)-mediated antibody effector functions. using transgenic mice expressing human cd20, we found that chronic lcmv infection impaired the depletion of b cells with rituximab, an anti-cd20 antibody widely used for the treat ... | 2015 | 25680276 |
| targeting of non-dominant antigens as a vaccine strategy to broaden t-cell responses during chronic viral infection. | in this study, we compared adenoviral vaccine vectors with the capacity to induce equally potent immune responses against non-dominant and immunodominant epitopes of murine lymphocytic choriomeningitis virus (lcmv). our results demonstrate that vaccination targeting non-dominant epitopes facilitates potent virus-induced t-cell responses against immunodominant epitopes during subsequent challenge with highly invasive virus. in contrast, when an immunodominant epitope was included in the vaccine, ... | 2015 | 25679375 |
| deficiency of the b cell-activating factor receptor results in limited cd169+ macrophage function during viral infection. | the b cell-activating factor (baff) is critical for b cell development and humoral immunity in mice and humans. while the role of baff in b cells has been widely described, its role in innate immunity remains unknown. using baff receptor (baffr)-deficient mice, we characterized baffr-related innate and adaptive immune functions following infection with vesicular stomatitis virus (vsv) and lymphocytic choriomeningitis virus (lcmv). we identified a critical role for baffr signaling in the generati ... | 2015 | 25673724 |
| t cell expansion is the limiting factor of virus control in mice with attenuated tcr signaling: implications for human immunodeficiency. | defining the minimal thresholds for effective antiviral t cell immunity is important for clinical decisions in immunodeficient patients. tcr signaling is critical for t cell development, activation, and effector functions. in this article, we analyzed which of these tcr-mediated processes is limiting for antiviral immunity in a mouse strain with reduced expression of slp-76 (twp mice). despite severe t cell activation defects in vitro, twp mice generated a normal proportion of antiviral effector ... | 2015 | 25672755 |
| cutaneous rank-rankl signaling upregulates cd8-mediated antiviral immunity during herpes simplex virus infection by preventing virus-induced langerhans cell apoptosis. | herpes simplex virus-type 1 (hsv-1) causes the majority of cutaneous viral infections. viral infections are controlled by the immune system, and cd8(+) cytotoxic t-lymphocytes (ctls) have been shown to be crucial during the clearance of hsv-1 infections. although epidermal langerhans cells (lcs) are the first dendritic cells (dcs) to come into contact with the virus, it has been shown that the processing of viral antigens and the differentiation of antiviral ctls are mediated by migratory cd103( ... | 2015 | 26076314 |
| tropism of cpmv to professional antigen presenting cells enables a platform to eliminate chronic infections. | chronic viral infections (e.g., hiv, hbv, hcv) represent a significant source of morbidity and mortality with over 500 million people infected worldwide. dendritic cells (dcs) and macrophages are key cell types for productive viral replication and persistent systemic infection. we demonstrate that the plant virus cowpea mosaic virus (cpmv) displays tropism for such antigen presenting cells in both mice and humans, thus making it an ideal candidate for targeted drug delivery toward viral infectio ... | 2015 | 27280157 |
| lassa-vesicular stomatitis chimeric virus safely destroys brain tumors. | high-grade tumors in the brain are among the deadliest of cancers. here, we took a promising oncolytic virus, vesicular stomatitis virus (vsv), and tested the hypothesis that the neurotoxicity associated with the virus could be eliminated without blocking its oncolytic potential in the brain by replacing the neurotropic vsv glycoprotein with the glycoprotein from one of five different viruses, including ebola virus, marburg virus, lymphocytic choriomeningitis virus (lcmv), rabies virus, and lass ... | 2015 | 25878115 |
| ebola virus and severe acute respiratory syndrome coronavirus display late cell entry kinetics: evidence that transport to npc1+ endolysosomes is a rate-defining step. | ebola virus (ebov) causes hemorrhagic fevers with high mortality rates. during cellular entry, the virus is internalized by macropinocytosis and trafficked through endosomes until fusion between the viral and an endosomal membrane is triggered, releasing the rna genome into the cytoplasm. we found that while macropinocytotic uptake of filamentous ebov viruslike particles (vlps) expressing the ebov glycoprotein (gp) occurs relatively quickly, vlps only begin to enter the cytoplasm after a 30-min ... | 2015 | 25552710 |
| sero-prevalence of rodent pathogens in india. | health monitoring is an integral part of laboratory animal quality standards. however, current or past prevalence data as well as regulatory requirements dictate the frequency, type and the expanse of health monitoring. in an effort to understand the prevalence of rodent pathogens in india, a preliminary study was carried out by sero-epidemiology. sera samples obtained from 26 public and private animal facilities were analyzed for the presence of antibodies against minute virus of mice (mvm), ec ... | 2015 | 26158453 |
| interaction between unrelated viruses during in vivo co-infection to limit pathology and immunity. | great progress has been made in understanding immunity to viral infection. however, infection can occur in the context of co-infection by unrelated pathogens that modulate immune responses and/or disease. we have studied immunity and disease during co-infection with two unrelated viruses: ectromelia virus (ectv) and lymphocytic choriomeningitis virus (lcmv). ectv infection can be a lethal in mice due in part to the blockade of type i interferons (ifn-i). we show that ectv/lcmv co-infection resul ... | 2015 | 26099694 |
| prostaglandin e2 and programmed cell death 1 signaling coordinately impair ctl function and survival during chronic viral infection. | more than 10% of the world's population is chronically infected with hiv, hepatitis c virus (hcv) or hepatitis b virus (hbv), all of which can cause severe disease and death. these viruses persist in part because continuous antigenic stimulation causes the deterioration of virus-specific cytotoxic t lymphocyte (ctl) function and survival. additionally, antiviral ctls autonomously suppress their responses to limit immunopathology by upregulating inhibitory receptors such as programmed cell death ... | 2015 | 25799228 |
| t-cell exhaustion in chronic hepatitis b infection: current knowledge and clinical significance. | hepatitis b virus (hbv) infection is the major cause of inflammatory liver disease, of which the clinical recovery and effective anti-viral therapy is associated with the sustained viral control of effector t cells. in humans, chronic hbv infection often shows weak or absent virus-specific t-cell reactivity, which is described as the 'exhaustion' state characterized by poor effector cytotoxic activity, impaired cytokine production and sustained expression of multiple inhibitory receptors, such a ... | 2015 | 25789969 |
| expression of viral antigen by the liver leads to chronic infection through the generation of regulatory t cells. | the constant exposure of the liver to food and bacterial antigens through the mesenteric circulation requires it to maintain tolerance while preserving the ability to mount an effective immune response against pathogens. we investigated the contribution of the liver's tolerogenic nature on the establishment of chronic viral infections. | 2015 | 28210682 |
| inflammatory monocytes recruited to the liver within 24 hours after virus-induced inflammation resemble kupffer cells but are functionally distinct. | due to a scarcity of immunocompetent animal models for viral hepatitis, little is known about the early innate immune responses in the liver. in various hepatotoxic models, both pro- and anti-inflammatory activities of recruited monocytes have been described. in this study, we compared the effect of liver inflammation induced by the toll-like receptor 4 ligand lipopolysaccharide (lps) with that of a persistent virus, lymphocytic choriomeningitis virus (lcmv) clone 13, on early innate intrahepati ... | 2015 | 25673700 |
| human hemorrhagic fever causing arenaviruses: molecular mechanisms contributing to virus virulence and disease pathogenesis. | arenaviruses include multiple human pathogens ranging from the low-risk lymphocytic choriomeningitis virus (lcmv) to highly virulent hemorrhagic fever (hf) causing viruses such as lassa (lasv), junin (junv), machupo (macv), lujo (lujv), sabia (sabv), guanarito (gtov), and chapare (chpv), for which there are limited preventative and therapeutic measures. why some arenaviruses can cause virulent human infections while others cannot, even though they are isolated from the same rodent hosts, is an e ... | 2015 | 26011826 |
| cd39 expression identifies terminally exhausted cd8+ t cells. | exhausted t cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. defining novel markers of exhaustion is important both for identifying and potentially reversing t cell exhaustion. herein, we show that the ectonucleotidse cd39 is a marker of exhausted cd8+ t cells. cd8+ t cells specific for hcv or hiv express high levels of cd39, but those specific for ebv and cmv do not. cd39 expressed by cd8+ t cells in chronic infection is en ... | 2015 | 26485519 |
| fas regulates neutrophil lifespan during viral and bacterial infection. | the regulation of neutrophil lifespan is critical for a circumscribed immune response. neutrophils are sensitive to fas/cd95 death receptor signaling in vitro, but it is unknown if fas regulates neutrophil lifespan in vivo. we hypothesized that fasl-expressing cd8(+) t cells, which kill antigen-stimulated t cells during chronic viral infection, can also induce neutrophil death in tissues during infection. with the use of lysm-cre fas(fl/fl) mice, which lack fas expression in macrophages and neut ... | 2015 | 25473101 |
| novel mechanism of arenavirus-induced liver pathology. | viral hemorrhagic fevers (vhfs) encompass a group of diseases with cardinal symptoms of fever, hemorrhage, and shock. the liver is a critical mediator of vhf disease pathogenesis and high levels of alt/ast transaminases in plasma correlate with poor prognosis. in fact, lassa fever (lf), the most prevalent vhf in africa, was initially clinically described as hepatitis. previous studies in non-human primate (nhp) models also correlated lf pathogenesis with a robust proliferative response in the li ... | 2015 | 25822203 |
| therapeutic antiviral t cells noncytopathically clear persistently infected microglia after conversion into antigen-presenting cells. | several viruses can infect the mammalian nervous system and induce neurological dysfunction. adoptive immunotherapy is an approach that involves administration of antiviral t cells and has shown promise in clinical studies for the treatment of peripheral virus infections in humans such as cytomegalovirus (cmv), epstein-barr virus (ebv), and adenovirus, among others. in contrast, clearance of neurotropic infections is particularly challenging because the central nervous system (cns) is relatively ... | 2015 | 26122661 |
| double-stranded rna is detected by immunofluorescence analysis in rna and dna virus infections, including those by negative-stranded rna viruses. | early biochemical studies of viral replication suggested that most viruses produce double-stranded rna (dsrna), which is essential for the induction of the host immune response. however, it was reported in 2006 that dsrna could be detected by immunofluorescence antibody staining in double-stranded dna and positive-strand rna virus infections but not in negative-strand rna virus infections. other reports in the literature seemed to support these observations. this suggested that negative-strand r ... | 2015 | 26136565 |
| nk cells inhibit humoral immunity by reducing the abundance of cd4+ t follicular helper cells during a chronic virus infection. | there is a need to understand better how to improve b cell responses and immunity to persisting virus infections, which often cause debilitating illness or death. people with chronic virus infection show evidence of improved virus control when there is a strong neutralizing antibody response, and conversely, b cell dysfunction is associated with higher viral loads. we showed previously that nk cells inhibit cd4(+) and cd8(+) t cell responses to disseminating lcmv infection and that depletion of ... | 2015 | 25986014 |
| evidence of human infection by a new mammarenavirus endemic to southeastern asia. | southeastern asia is a recognised hotspot for emerging infectious diseases, many of which have an animal origin. mammarenavirus infections contribute significantly to the human disease burden in both africa and the americas, but little data exists for asia. to date only two mammarenaviruses, the widely spread lymphocytic choriomeningitis virus and the recently described wēnzhōu virus have been identified in this region, but the zoonotic impact in asia remains unknown. here we report the presence ... | 2016 | 27278118 |
| zoonotic and vector-borne infections among urban homeless and marginalized people in the united states and europe, 1990-2014. | in high-income countries, homeless individuals in urban areas often live in crowded conditions with limited sanitation and personal hygiene. the environment of homelessness in high-income countries may result in intensified exposure to ectoparasites and urban wildlife, which can transmit infections. to date, there have been no systematic evaluations of the published literature to assess vector-borne and zoonotic disease risk to these populations. | 2016 | 27159039 |
| replication-defective lymphocytic choriomeningitis virus vectors expressing guinea pig cytomegalovirus gb and pp65 homologs are protective against congenital guinea pig cytomegalovirus infection. | congenital cytomegalovirus infection can be life-threatening and often results in significant developmental deficits and/or hearing loss. thus, there is a critical need for an effective anti-cmv vaccine. | 2016 | 26973071 |
| companion animals as a source of viruses for human beings and food production animals. | companion animals comprise a wide variety of species, including dogs, cats, horses, ferrets, guinea pigs, reptiles, birds and ornamental fish, as well as food production animal species, such as domestic pigs, kept as companion animals. despite their prominent place in human society, little is known about the role of companion animals as sources of viruses for people and food production animals. therefore, we reviewed the literature for accounts of infections of companion animals by zoonotic viru ... | 2016 | 27522300 |
| molecular survey of zoonotic agents in rodents and other small mammals in croatia. | croatia is a focus for many rodent-borne zoonosis. here, we report a survey of 242 rodents and small mammals, including 43 myodes glareolus, 131 apodemus flavicollis, 53 apodemus agrarius, three apodemus sylvaticus, six sorex araneus, four microtus arvalis, one microtus agrestis, and one muscardinus avellanarius, collected at eight sites in croatia over an 8-year period. multiplex masstag polymerase chain reaction (pcr) was used for detection of borrelia, rickettsia, bartonella, babesia, ehrlich ... | 2016 | 26711522 |
| attenuated viral hepatitis in trem1-/- mice is associated with reduced inflammatory activity of neutrophils. | trem1 (triggering receptor expressed on myeloid cells 1) is a pro-inflammatory receptor expressed by phagocytes, which can also be released as a soluble molecule (strem1). the roles of trem1 and strem1 in liver infection and inflammation are not clear. here we show that patients with hepatitis b virus (hbv) or hepatitis c virus (hcv) infection manifest elevated serum levels of strem1. in mice, experimental viral hepatitis induced by infection with lymphocytic choriomeningitis virus (lcmv)-we was ... | 2016 | 27328755 |
| identification and characterization of a novel broad-spectrum virus entry inhibitor. | virus entry into cells is a multistep process that often requires the subversion of subcellular machineries. a more complete understanding of these steps is necessary to develop new antiviral strategies. while studying the potential role of the actin network and one of its master regulators, the small gtpase cdc42, during junin virus (junv) entry, we serendipitously uncovered the small molecule zcl278, reported to inhibit cdc42 function as an entry inhibitor for junv and for vesicular stomatitis ... | 2016 | 26912630 |
| inclusion of epitopes that expand high-avidity cd4+ t cells transforms subprotective vaccines to efficacious immunogens against virulent francisella tularensis. | t cells are the immunological cornerstone in host defense against infections by intracellular bacterial pathogens, such as virulent francisella tularensis spp. tularensis (ftt). the general paucity of novel vaccines for ftt during the past 60 y can, in part, be attributed to the poor understanding of immune parameters required to survive infection. thus, we developed a strategy utilizing classical immunological tools to elucidate requirements for effective adaptive immune responses directed agai ... | 2016 | 27543611 |
| alcohol intake alters immune responses and promotes cns viral persistence in mice. | chronic hepatitis c virus (hcv) infection leads to progressive liver disease and is associated with a variety of extrahepatic effects, including central nervous system (cns) damage and neuropsychiatric impairments. alcohol abuse can exacerbate these adverse effects on brain and behavior, but the molecular mechanisms are not well understood. this study investigated the role of alcohol in regulating viral persistence and cns immunopathology in mice infected with lymphocytic choriomeningitis virus ... | 2016 | 27269869 |
| immune-surveillance through exhausted effector t-cells. | pathogens such as the human immunodeficiency virus (hiv), the hepatitis b and c virus (hbv, hcv) and certain strains of the rodent lymphocytic choriomeningitis virus (lcmv) establish a state of persisting viral replication. this occurs besides strong adoptive immune responses and the induction of large numbers of activated pathogen-specific t-cells. the failure of the immune system to clear these viruses is typically attributed to a loss of effector t-cell function-a phenomenon referred to as t- ... | 2016 | 26826950 |
| il2rβ-dependent signals drive terminal exhaustion and suppress memory development during chronic viral infection. | exhaustion of cd8(+) t cells severely impedes the adaptive immune response to chronic viral infections. despite major advances in our understanding of the molecular regulation of exhaustion, the cytokines that directly control this process during chronicity remain unknown. we demonstrate a direct impact of il-2 and il-15, two common gamma-chain-dependent cytokines, on cd8(+) t-cell exhaustion. common to both cytokine receptors, the il-2 receptor β (il2rβ) chain is selectively maintained on cd8(+ ... | 2016 | 27573835 |
| ctla-4 blockade plus adoptive t-cell transfer promotes optimal melanoma immunity in mice. | immunotherapeutic approaches to the treatment of advanced melanoma have relied on strategies that augment the responsiveness of endogenous tumor-specific t-cell populations [eg, cytotoxic t lymphocyte-associated antigen 4 (ctla-4) blockade-mediated checkpoint inhibition] or introduce exogenously prepared tumor-specific t-cell populations [eg, adoptive cell transfer (act)]. although both approaches have shown considerable promise, response rates to these therapies remain suboptimal. we hypothesiz ... | 2016 | 25658614 |
| novel model of double transgenic mouse results in autoimmune diabetes in males. | identifying the type of diabetogenic cd8(+) t cells that initiate autoimmune diabetes (aid) is a critical step in designing appropriate strategies for the early detection of beta cell-directed autoimmunity and its progression to diabetes. we generated a novel double transgenic (tg) mouse model on the naturally diabetes resistant c57bl/6 background, co-expressing two transgenes including a specific tcr anti-lymphocytic choriomeningitis virus nucleoprotein (lcmv-np) carried by cd8(+) t cells and l ... | 2016 | 27683954 |
| antigen exposure shapes the ratio between antigen-specific tregs and conventional t cells in human peripheral blood. | the t-cell receptor (tcr) is required for maturation and function of regulatory t cells (tregs), but the ligand specificities of tregs outside the context of transgenic tcrs are largely unknown. using peptide-mhc tetramers, we isolated rare specific foxp3(+) cells directly ex vivo from adult peripheral blood and defined their frequency and phenotype. we find that a proportion of circulating tregs recognize foreign antigens and the frequency of these cells are similar to that of self-reactive tre ... | 2016 | 27681619 |
| t-cells underlie some but not all of the cerebellar pathology in a neonatal rat model of congenital lymphocytic choriomeningitis virus infection. | lymphocytic choriomeningitis virus (lcmv) infection during pregnancy injures the human fetal brain. neonatal rats inoculated with lcmv are an excellent model of congenital lcmv infection because they develop cerebellar injuries similar to those in humans. to evaluate the role of t-lymphocytes in lcmv-induced cerebellar pathology, congenitally athymic rats, deficient in t-lymphocytes were compared with euthymic rats. peak viral titers and cellular targets of infection were similar, but viral clea ... | 2016 | 27667772 |
| t-cell exhaustion: understanding the interface of chronic viral and autoinflammatory diseases. | during acute viral infection cd8 t cells rapidly expand before contracting down to a persistent memory population that confers long-lasting immunity. however when the antigen persists, such as during chronic viral infection, a dysfunctional process termed 'exhaustion' limits the antiviral response, facilitating ongoing viraemia and poor clinical outcome. cd8 t-cell exhaustion was originally identified in lymphocytic choriomeningitis virus infection of mice; however, new evidence has shown that e ... | 2016 | 27577866 |
| tcr independent suppression of cd8(+) t cell cytokine production mediated by ifnγ in vivo. | cd8(+) memory t cells produce ifnγ within hours of secondary infection, but this is quickly terminated in vivo despite the presence of stimulatory viral antigen, suggesting that active suppression occurs. herein, we investigated the in vivo effector function of cd8(+) memory t cells during successive encounters with viral antigen. cd8(+) t cells in immune mice receiving prior viral or peptide challenge failed to reproduce ifnγ during lcmv rechallenge. surprisingly, this refractory state was indu ... | 2016 | 27564543 |
| dendritic cells are dispensable for t cell priming and control of acute lymphocytic choriomeningitis virus infection. | dendritic cells (dcs) are considered to be the major apcs with potent activity for priming of naive cd4 and cd8 t cells. however, t cell priming can also be achieved by other apcs including macrophages, b cells, or even nonhematopoietic cell types. systemic low-dose infection of mice with lymphocytic choriomeningitis virus (lcmv) results in massive expansion of virus-specific cd4 and cd8 t cells. to determine the role of dcs as apcs and source of type i ifns in this infection model, we used δdc ... | 2016 | 27549169 |
| t cell factor 1-expressing memory-like cd8(+) t cells sustain the immune response to chronic viral infections. | chronic infections promote the terminal differentiation (or "exhaustion") of t cells and are thought to preclude the formation of memory t cells. in contrast, we discovered a small subpopulation of virus-specific cd8(+) t cells that sustained the t cell response during chronic infections. these cells were defined by, and depended on, the expression of the transcription factor tcf1. transcriptome analysis revealed that this population shared key characteristics of central memory cells but lacked ... | 2016 | 27533016 |
| defining cd8+ t cells that provide the proliferative burst after pd-1 therapy. | chronic viral infections are characterized by a state of cd8(+) t-cell dysfunction that is associated with expression of the programmed cell death 1 (pd-1) inhibitory receptor. a better understanding of the mechanisms that regulate cd8(+) t-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted cd8(+) t cells. here we identify a population of virus-specific cd8(+) t cells that proliferate after blockade of the pd-1 inhibitory pathway in ... | 2016 | 27501248 |
| bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor pd-1 are an early driver of cd8(+) t cell exhaustion. | dynamic reprogramming of metabolism is essential for t cell effector function and memory formation. however, the regulation of metabolism in exhausted cd8(+) t (tex) cells is poorly understood. we found that during the first week of chronic lymphocytic choriomeningitis virus (lcmv) infection, before severe dysfunction develops, virus-specific cd8(+) t cells were already unable to match the bioenergetics of effector t cells generated during acute infection. suppression of t cell bioenergetics inv ... | 2016 | 27496729 |
| high level of perforin expression is required for effective correction of hemophagocytic lymphohistiocytosis. | perforin-1 mutations result in a potentially fatal hemophagocytic lymphohistiocytosis (hlh) with heightened immune activation, hypercytokinemia, pancytopenia, and end-organ damage. at present, hematopoietic stem cell (hsc) transplantation is curative, but limited by donor availability and associated mortality, making gene therapy an attractive alternative approach for hlh. we reported that perforin expression driven by cellular promoters in lentiviral (lv) vectors resulted in significant, albeit ... | 2016 | 27471778 |
| demethylation of the pd-1 promoter is imprinted during the effector phase of cd8 t cell exhaustion. | pd-1 is an inhibitory receptor that has a major role in t cell dysfunction during chronic infections and cancer. while demethylation of the pd-1 promoter dna is observed in exhausted t cells isolated from chronically infected individuals, little is known about when this stable demethylation of pd-1 promoter dna is programmed during the course of a chronic infection. to assess if pd-1 promoter dna demethylation is impacted by prolonged stimulation during effector phase of chronic infection, we ad ... | 2016 | 27466420 |
| targeting t cell bioenergetics by modulating p-glycoprotein selectively depletes alloreactive t cells to prevent graft-versus-host disease. | t lymphocytes play a central role in many human immunologic disorders, including autoimmune and alloimmune diseases. in hematopoietic stem cell transplantation, acute graft-versus-host-disease (gvhd) is caused by an attack on the recipient's tissues from donor allogeneic t cells. selectively depleting gvhd-causing cells prior to transplant may prevent gvhd. in this study, we evaluated 24 chalcogenorhodamine photosensitizers for their ability to selectively deplete reactive t lymphocytes and iden ... | 2016 | 27456485 |
| high antigen levels induce an exhausted phenotype in a chronic infection without impairing t cell expansion and survival. | chronic infections induce t cells showing impaired cytokine secretion and up-regulated expression of inhibitory receptors such as pd-1. what determines the acquisition of this chronic phenotype and how it impacts t cell function remain vaguely understood. using newly generated recombinant antigen variant-expressing chronic lymphocytic choriomeningitis virus (lcmv) strains, we uncovered that t cell differentiation and acquisition of a chronic or exhausted phenotype depend critically on the freque ... | 2016 | 27455951 |
| a novel phosphoserine motif in the lcmv matrix protein z regulates the release of infectious virus and defective interfering particles. | we report that the lymphocytic choriomeningitis virus (lcmv) matrix protein, which drives viral budding, is phosphorylated at serine 41 (s41). a recombinant (r)lcmv bearing a phosphomimetic mutation (s41d) was impaired in infectious and defective interfering (di) particle release, while a non-phosphorylatable mutant (s41a) was not. the s41d mutant was disproportionately impaired in its ability to release di particles relative to infectious particles. thus, di particle production by lcmv may be d ... | 2016 | 27421645 |
| phenotypic and functional analysis of activated regulatory t cells isolated from chronic lymphocytic choriomeningitis virus-infected mice. | regulatory t (treg) cells, which express foxp3 as a transcription factor, are subsets of cd4(+) t cells. treg cells play crucial roles in immune tolerance and homeostasis maintenance by regulating the immune response. the primary role of treg cells is to suppress the proliferation of effector t (teff) cells and the production of cytokines such as ifn-γ, tnf-α, and il-2. it has been demonstrated that treg cells' ability to inhibit the function of teff cells is enhanced during persistent pathogen ... | 2016 | 27404802 |
| il-10 regulates memory t cell development and the balance between th1 and follicular th cell responses during an acute viral infection. | t cells provide protective immunity against infections by differentiating into effector cells that contribute to rapid pathogen control and by forming memory populations that survive over time and confer long-term protection. thus, understanding the factors that regulate the development of effective t cell responses is beneficial for the design of vaccines and immune-based therapies against infectious diseases. cytokines play important roles in shaping t cell responses, and il-10 has been shown ... | 2016 | 27402701 |
| ccr7 expression alters memory cd8 t-cell homeostasis by regulating occupancy in il-7- and il-15-dependent niches. | c-c receptor 7 (ccr7) is important to allow t cells and dendritic cells to migrate toward ccl19- and ccl21-producing cells in the t-cell zone of the spleen and lymph nodes. the role of this chemokine receptor in regulating the homeostasis of effector and memory t cells during acute viral infection is poorly defined, however. in this study, we show that ccr7 expression alters memory cd8 t-cell homeostasis following lymphocytic choriomeningitis virus infection. greater numbers of ccr7-deficient me ... | 2016 | 27385825 |
| interleukin-21-dependent modulation of t cell antigen receptor reactivity towards low affinity peptide ligands in autoreactive cd8(+) t lymphocytes. | il-21 promotes autoimmune type-1 diabetes (t1d) in nod mice by facilitating cd4(+) t cell help to cd8(+) t cells. il-21 also enables autoreactive cd8(+) t cells to respond to weak tcr ligands and induce t1d. here, we assessed whether il-21 is essential for t1d induction in a mouse model where the disease can occur independently of cd4 help. in this model, which expresses lymphocytic choriomeningitis virus (lcmv) glycoprotein (gp) antigen under the rat insulin promoter (rip-gp), lcmv infection ac ... | 2016 | 27300756 |
| il-4 sensitivity shapes the peripheral cd8+ t cell pool and response to infection. | previous studies have revealed that a population of innate memory cd8(+) t cells is generated in response to il-4, first appearing in the thymus and bearing high expression levels of eomesodermin (eomes) but not t-bet. however, the antigen specificity and functional properties of these cells is poorly defined. in this study, we show that il-4 regulates not only the frequency and function of innate memory cd8(+) t cells, but also regulates eomes expression levels and functional reactivity of naiv ... | 2016 | 27298446 |
| alterations in cellular metabolism modulate cd1d-mediated nkt-cell responses. | natural killer t (nkt) cells play a critical role in the host's innate immune response. cd1d-mediated presentation of glycolipid antigens to nkt cells has been established; however, the mechanisms by which nkt cells recognize infected or cancerous cells remain unclear. 5(')-amp activated protein kinase (ampk) is a master regulator of lipogenic pathways. we hypothesized that activation of ampk during infection and malignancy could alter the repertoire of antigens presented by cd1d and serve as a ... | 2016 | 27297969 |
| development and application of elisa for the detection of igg antibodies to lymphocytic choriomeningitis virus. | lymphocytic choriomeningitis virus (lcmv) is a neglected human pathogen, which can cause severe illnesses in humans. the most vulnerable are the human foetus and immunosuppressed individuals. since there is no commercially available enzyme-linked immunosorbent assay (elisa) for the diagnosis of anti-lcmv antibodies in human sera, we developed a sandwich elisa method detecting anti-nucleoprotein igg antibodies, using a specific monoclonal anti-nucleoprotein antibody and cells persistently infecte ... | 2016 | 27265463 |
| psgl-1 is an immune checkpoint regulator that promotes t cell exhaustion. | chronic viruses and cancers thwart immune responses in humans by inducing t cell dysfunction. using a murine chronic virus that models human infections, we investigated the function of the adhesion molecule, p-selectin glycoprotein ligand-1 (psgl-1), that is upregulated on responding t cells. psgl-1-deficient mice cleared the virus due to increased intrinsic survival of multifunctional effector t cells that had downregulated pd-1 as well as other inhibitory receptors. notably, this response resu ... | 2016 | 27192578 |
| cd8 engineered cytotoxic t cells reprogram melanoma tumor environment. | cytotoxic t lymphocytes (ctl) from cd8β-deficient mice have powerful fasl-mediated cytotoxicity and ifnγ responses, but ablated ca(2+) and nfat signaling, which can be restored by transduction with cd8β. upon infection with lymphocytic choriomeningitis virus (lcmv), these cells yielded gp33-specific ctl (cd8βr) that exhibited high fasl/fas-mediated cytotoxicity, ifnγ cxcl9 and 10 chemokine responses. transfer of these cells in b16-gp33 tumor bearing mice resulted in (i) massive t cell tumor infi ... | 2016 | 27141342 |
| prenatal brain mri of fetuses with zika virus infection. | an outbreak of zika virus was observed in french polynesia in 2013-2014. maternal zika virus infection has been associated with fetal microcephaly and severe cerebral damage. | 2016 | 27090801 |
| generation of lymphocytic choriomeningitis virus based vaccine vectors. | vaccination with a recombinant lcmv based vector expressing tumor-associated or viral antigens is a safe and versatile method to induce an immune response against tumors or viral infections. here, we describe the generation of recombinant lcmv vectors in which the gene encoding the viral lcmv-gp was substituted with a gene of interest (vaccine antigen). this renders the vaccine vector propagation-incompetent while it preserves the property of eliciting a strong cytotoxic t cell response. | 2016 | 27076310 |
| enhanced local and systemic anti-melanoma cd8+ t cell responses after memory t cell-based adoptive immunotherapy in mice. | adoptive cell transfer (act) melanoma immunotherapy typically employs acutely activated effector cd8+ t cells for their ability to rapidly recognize and clear antigen. we have previously observed that effector cd8+ t cells are highly susceptible to melanoma-induced suppression, whereas memory cd8+ t cells are not. although memory t cells have been presumed to be potentially advantageous for act, the kinetics of local and systemic t cell responses after effector and memory act have not been compa ... | 2016 | 27011014 |
| the lymphocytic choriomeningitis virus matrix protein ppxy late domain drives the production of defective interfering particles. | arenaviruses cause severe diseases in humans but establish asymptomatic, lifelong infections in rodent reservoirs. persistently-infected rodents harbor high levels of defective interfering (di) particles, which are thought to be important for establishing persistence and mitigating virus-induced cytopathic effect. little is known about what drives the production of di particles. we show that neither the ppxy late domain encoded within the lymphocytic choriomeningitis virus (lcmv) matrix protein ... | 2016 | 27010636 |
| errata: vol. 65, no. 9. | in the report, "notes from the field: lymphocytic choriomeningitis virus meningoencephalitis from a household rodent infestation - minnesota, 2015," on page 248, the first sentence of the fourth paragraph should read, "the family was referred for integrated pest management services through the st. paul-ramsey county department of public health, with assistance from the minnesota department of health healthy homes grant program." | 2016 | 27010589 |
| high frequencies of anti-host reactive cd8+ t cells ignore non-hematopoietic antigen after bone marrow transplantation in a murine model. | graft versus host disease (gvhd) occurs in 20% of cases with patients having an mhc i matched bone marrow transplantation (bmt). mechanisms causing this disease remain to be studied. | 2016 | 27007114 |
| lymphocytic choriomeningitis virus: ways to establish and maintain non-cytolytic persistent infection. | lymphocytic choriomeningitis virus (lcmv) is a prototype virus of the arenaviridae family that is attracting considerable attention both as an important experimental model system to study acute and persistent viral infections, and as a neglected human pathogen of clinical significance. notably, lcmv is capable of persisting in an infected host, and escaping the immune system. here we describe the strategies used by the virus to establish and maintain long-term infection in vitro and/or persisten ... | 2016 | 26982463 |
| il-10 induces t cell exhaustion during transplantation of virus infected hearts. | unexpected transmissions of viral pathogens during solid organ transplantation (sot) can result in severe, life-threatening diseases in transplant recipients. immune activation contributes to disease onset. however mechanisms balancing the immune response against transmitted viral infection through organ transplantation remain unknown. methods & | 2016 | 26963287 |
| il-2 consumption by highly activated cd8 t cells induces regulatory t-cell dysfunction in patients with hemophagocytic lymphohistiocytosis. | hemophagocytic lymphohistiocytosis (hlh) is a severe inflammatory condition driven by excessive cd8(+) t-cell activation. hlh occurs as both acquired and familial hemophagocytic lymphohistiocytosis (fhl) forms. in both conditions, a sterile or infectious trigger is required for disease initiation, which then becomes self-sustaining and life-threatening. recent studies have attributed the key distal event to excessive ifn-γ production; however, the proximal events driving immune dysregulation hav ... | 2016 | 26947179 |
| viral escape mutant epitope maintains tcr affinity for antigen yet curtails cd8 t cell responses. | t cells have the remarkable ability to recognize antigen with great specificity and in turn mount an appropriate and robust immune response. critical to this process is the initial t cell antigen recognition and subsequent signal transduction events. this antigen recognition can be modulated at the site of tcr interaction with peptide:major histocompatibility (pmhc) or peptide interaction with the mhc molecule. both events could have a range of effects on t cell fate. though responses to antigen ... | 2016 | 26915099 |
| novel drug discovery approaches for treating arenavirus infections. | arenaviruses are enveloped negative stranded viruses endemic in africa, europe and the americas. several arenaviruses cause severe viral hemorrhagic fever with high mortality in humans and pose serious public health threats. so far, there are no fda-approved vaccines and therapeutic options are restricted to the off-label use of ribavirin. the major human pathogenic arenaviruses are classified as category a agents and require biosafety level (bsl)-4 containment. | 2016 | 26882218 |
| polygenic mutations in the cytotoxicity pathway increase susceptibility to develop hlh immunopathology in mice. | hemophagocytic lymphohistiocytosis (hlh) is a life-threatening hyperinflammatory disease. inherited forms of hlh are caused by biallelic mutations in several effectors of granule-dependent lymphocyte-mediated cytotoxicity. a small proportion of patients with a so-called "secondary" form of hlh, which develops in the aftermath of infection, autoimmunity, or cancer, carry a monoallelic mutation in one or more hlh-associated genes. although this observation suggests that hlh may have a polygenic mo ... | 2016 | 26864340 |
| mcl-1 regulates effector and memory cd8 t-cell differentiation during acute viral infection. | mcl-1, an anti-apoptotic member of bcl-2 family maintains cell viability during clonal expansion of cd8 t cells, but the cell intrinsic role of mcl-1 in contraction of effectors or the number of memory cd8 t cells is unknown. mcl-1 levels decline during the contraction phase but rebound to high levels in memory cd8 t cells. therefore, by overexpressing mcl-1 in cd8 t cells we asked whether limiting levels of mcl-1 promote contraction of effectors and constrain cd8 t-cell memory. mcl-1 overexpres ... | 2016 | 26855329 |
| a context-dependent role for il-21 in modulating the differentiation, distribution, and abundance of effector and memory cd8 t cell subsets. | the activation of naive cd8 t cells typically results in the formation of effector cells (te) as well as phenotypically distinct memory cells that are retained over time. memory cd8 t cells can be further subdivided into central memory, effector memory (tem), and tissue-resident memory (trm) subsets, which cooperate to confer immunological protection. using mixed bone marrow chimeras and adoptive transfer studies in which cd8 t cells either do or do not express il-21r, we discovered that under h ... | 2016 | 26826252 |
| janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis. | hemophagocytic lymphohistiocytosis (hlh) comprises an emerging spectrum of inherited and noninherited disorders of the immune system characterized by the excessive production of cytokines, including interferon-γ and interleukins 2, 6, and 10 (il-2, il-6, and il-10). the janus kinases (jaks) transduce signals initiated following engagement of specific receptors that bind a broad array of cytokines, including those overproduced in hlh. based on the central role for cytokines in the pathogenesis of ... | 2016 | 26825707 |