bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunoproteasomes Are Essential for Clearance ofListeria monocytogenesin Nonlymphoid Tissues but Not for Induction of Bacteria-Specific CD8+ T Cells
Authors: Strehl Britta , Joeris Thorsten , Rieger Melanie , Visekruna Alexander , Textoris-Taube Kathrin , Kaufmann Stefan H. E. , Kloetzel Peter-Michael , Kuckelkorn Ulrike , Steinhoff Ulrich 
Published: April 2014

AbstractMicrobial infections induce the replacement of constitutive proteasomes by immunoproteasomes (I-proteasomes). I-proteasomes support efficient generation of MHC class I epitopes and influence immunodominance hierarchies of CD8+ T cells. Recently, the function of I-proteasomes in antimicrobial responses was challenged by showing that the lack of I-proteasomes has no effect on induction and function of lymphocytic choriomeningitis virus-specific CD8+ T cells. Here, we show that infection with Listeria monocytogenes rapidly induces I-proteasomes in nonlymphoid tissues, which leads to enhanced generation of protection relevant CD8+ T cell epitopes. I-proteasome-deficient mice (β5i−/− mice) exhibited normal frequencies of L. monocytogenes-specific CD8+ T cells. However, clearance of L. monocytogenes in liver but not spleen was significantly impaired in I-proteasome-deficient mice. In summary, our studies demonstrate that induction of I-proteasomes is required for CD8+ T cell-mediated elimination of L. monocytogenes from nonlymphoid but not lymphoid tissues.
Mycobacterium tuberculosisSubverts Innate Immunity to Evade Specific Effectors
Authors: Loeuillet Corinne , Martinon Fabio , Perez Cynthia , Munoz Miguel , Thome Margot , Meylan Pascal R. 
Published: April 2014

AbstractThe macrophage is the niche of the intracellular pathogen Mycobacterium tuberculosis. Induction of macrophage apoptosis by CD4+ or CD8+ T cells is accompanied by reduced bacterial counts, potentially defining a host defense mechanism. We have already established that M. tuberculosis-infected primary human macrophages have a reduced susceptibility to Fas ligand (FasL)-induced apoptosis. To study the mechanisms by which M. tuberculosis prevents apoptotic signaling, we have generated a cell culture system based on PMA- and IFN-γ-differentiated THP-1 cells recapitulating the properties of primary macrophages. In these cells, nucleotide-binding oligomerization domain 2 or TLR2 agonists and mycobacterial infection protected macrophages from apoptosis and resulted in NF-κB nuclear translocation associated with up-regulation of the antiapoptotic cellular FLIP. Transduction of a receptor-interacting protein-2 dominant-negative construct showed that nucleotide-binding oligomerization domain 2 is not involved in protection in the mycobacterial infection system. In contrast, both a dominant-negative construct of the MyD88 adaptor and an NF-κB inhibitor abrogated the protection against FasL-mediated apoptosis, showing the implication of TLR2-mediated activation of NF-κB in apoptosis protection in infected macrophages. The apoptosis resistance of infected macrophages might be considered as an immune escape mechanism, whereby M. tuberculosis subverts innate immunity signaling to protect its host cell against FasL+-specific cytotoxic lymphocytes.
Mechanisms of Neonatal Mucosal Antibody Protection
Authors: Harris Nicola L. , Spoerri Iris , Schopfer Jacqueline F. , Nembrini Chiara , Merky Patrick , Massacand Joanna , Urban Joseph F. , Lamarre Alain , Burki Kurt , Odermatt Bernhard , Zinkernagel Rolf M. , Macpherson Andrew J. 
Published: April 2014

AbstractFollowing an abrupt transition at birth from the sterile uterus to an environment with abundant commensal and pathogenic microbes, neonatal mammals are protected by maternal Abs at mucosal surfaces. We show in mice that different Ab isotypes work in distinct ways to protect the neonatal mucosal surface. Secretory IgA acts to limit penetration of commensal intestinal bacteria through the neonatal intestinal epithelium: an apparently primitive process that does not require diversification of the primary natural Ab repertoire. In contrast, neonatal protection against the exclusively luminal parasite Heligmosomoides polygyrus required IgG from primed females. This immune IgG could either be delivered directly in milk or retrotransported via neonatal Fc receptor from the neonatal serum into the intestinal lumen to exert its protective effect.
Plasmacytoid Dendritic Cells Limit Viral Replication, Pulmonary Inflammation, and Airway Hyperresponsiveness in Respiratory Syncytial Virus Infection
Authors: Wang Hongwei , Peters Nina , Schwarze Jürgen 
Published: April 2014

AbstractPlasmacytoid dendritic cells (pDC), as major producers of IFN-α, are thought not only to be pivotal in antiviral immunity, but also to limit allergic inflammation. In this study, we delineate the role of pDC in a mouse model of respiratory syncytial virus (RSV)-induced airway inflammation. Bone marrow-derived pDC generated high levels of IFN-α upon RSV infection, and the percentage of pDC expressing MHC class II and maturation-associated costimulatory molecules was increased. However, their weak Ag-presenting capacity was not enhanced. Furthermore, pDC induced marked levels of IL-10 in T cell cultures irrespective of infection. In vivo, numbers of pDC in the lung increased early after RSV infection and remained elevated throughout the inflammatory phase and the resolution phase of infection. Depletion of pDC resulted in increases in peak RSV titers, pulmonary inflammation, and airway hyperresponsiveness. In contrast, adoptive transfer of activated pDC to the airways reduced RSV copy numbers. In conclusion, RSV infection induces activation of murine pDC with robust IFN-α production, limiting replication and accelerating elimination of RSV. In addition to this innate response, pDC also may play an immune regulatory role in reducing pulmonary inflammation and inhibiting the development of airway hyperresponsiveness.
Trypanosoma cruzi-Mediated IFN-γ-Inducible Nitric Oxide Output in Macrophages Is Regulated byiNOSmRNA Stability
Authors: Bergeron Marc , Olivier Martin 
Published: April 2014

AbstractAlthough the effects of activated macrophages (Μφ) on the intracellular parasite Trypanosoma cruzi are well documented, little is known about how host-Μφ functions are affected by this pathogen before activation. This study is aimed at assessing the capacity of T. cruzi infection to modulate J77.4 murine Μφ NO generation following IFN-γ stimulation, and identifying mechanisms regulating this modulation. Results show that parasite infection potentiates Μφ to produce inducible NO synthase (iNOS) mRNA and protein as well as NO following IFN-γ stimulation above IFN-γ alone controls. This potentiation occurs through the concomitant activation of NF-κB, ERK1/ERK2 MAPK, and stress-activated protein kinase signaling pathways. Activation of the JAK/STAT pathway by IFN-γ then leads to STAT1α translocation and the transcription of a stable iNOS mRNA species. A decreased rate of iNOS mRNA degradation results in elevated levels of iNOS protein and NO production. Maximal iNOS expression is likely achieved through NF-κB activation by T. cruzi, whereas iNOS mRNA stability results from ERK1/ERK2 MAPK and stress-activated protein kinase activation by the infection. Taken together, our data show that T. cruzi-infected Μφ NO generation is controlled at both pre- and posttranscriptional levels and relies on signaling pathway cross-talk. This is the first report of a parasite pathogen capable of heightening host mRNA stability.
The Engagement of Activating FcγRs Inhibits Primate Lentivirus Replication in Human Macrophages
Authors: David Annie , Sáez-Cirión Asier , Versmisse Pierre , Malbec Odile , Iannascoli Bruno , Herschke Florence , Lucas Marianne , Barré-Sinoussi Françoise , Mouscadet Jean-François , Daëron Marc , Pancino Gianfranco 
Published: April 2014

Abstract
We previously reported that the stimulation of monocyte-derived macrophages (MDM) by plate-bound i.v. Igs inhibits HIV-1 replication. In this study, we show that IgG immune complexes also suppress HIV-1 replication in MDMs and that activating receptors for the Fc portion of IgG–FcγRI, FcγRIIA, and FcγRIII–are responsible for the inhibition. MDM stimulation through FcγRs induces activation signals and the secretion of HIV-1 modulatory cytokines, such as M-CSF, TNF-α, and macrophage-derived chemokine. However, none of these cytokines contribute to HIV-1 suppression. HIV-1 entry and postintegration steps of viral replication are not affected, whereas reduced levels of reverse transcription products and of integrated proviruses, as determined by real-time PCR analysis, account for the suppression of HIV-1 gene expression in FcγR-activated MDMs. We found that FcγR-dependent activation of MDMs also inhibits the replication of HIV-2, SIVmac, and SIVagm, suggesting a common control mechanism for primate immunodeficiency lentiviruses in activated macrophages.
Akt/Protein Kinase B Modulates Macrophage Inflammatory Response toFrancisellaInfection and Confers a Survival Advantage in Mice
Authors: Rajaram Murugesan V. S. , Ganesan Latha P. , Parsa Kishore V. L. , Butchar Jonathan P. , Gunn John S. , Tridandapani Susheela 
Published: April 2014

AbstractThe Gram-negative bacterium Francisella novicida infects primarily monocytes/macrophages and is highly virulent in mice. Macrophages respond by producing inflammatory cytokines that confer immunity against the infection. However, the molecular details of host cell response to Francisella infection are poorly understood. In this study, we demonstrate that F. novicida infection of murine macrophages induces the activation of Akt. Inhibition of Akt significantly decreases proinflammatory cytokine production in infected macrophages, whereas production of the anti-inflammatory cytokine IL-10 is enhanced. Analysis of the mechanism of Akt influence on cytokine response demonstrated that Akt promotes NF-κB activation. We have extended these findings to show that Akt activation may be regulated by bacterial genes associated with phagosomal escape. Infection with mglA mutants of F. novicida elicited sustained activation of Akt in comparison to cells infected with wild-type F. novicida. Concomitantly, there was significantly higher proinflammatory cytokine production and lower IL-10 production in cells infected with the mglA mutant. Finally, transgenic animals expressing constitutively active Akt displayed a survival advantage over their wild-type littermates when challenged with lethal doses of F. novicida. Together, these observations indicate that Akt promotes proinflammatory cytokine production by F. novicida-infected macrophages through its influence on NF-κB, thereby contributing to immunity against F. novicida infection.
Enhancement of CD8+ T Cell Immunity in the Lung by CpG Oligodeoxynucleotides Increases Protective Efficacy of a Modified Vaccinia Ankara Vaccine against Lethal Poxvirus Infection Even in a CD4-Deficient Host
Authors: Belyakov Igor M. , Isakov Dmitry , Zhu Qing , Dzutsev Amiran , Klinman Dennis , Berzofsky Jay A. 
Published: April 2014

AbstractImmunostimulatory CpG oligodeoxynucleotides (ODN) have proven effective as adjuvants for protein-based vaccines, but their impact on immune responses induced by live viral vectors is not known. We found that addition of CpG ODN to modified vaccinia Ankara (MVA) markedly improved the induction of longer-lasting adaptive protective immunity in BALB/c mice against intranasal pathogenic vaccinia virus (Western Reserve; WR). Protection was mediated primarily by CD8+ T cells in the lung, as determined by CD8-depletion studies, protection in B cell-deficient mice, and greater protection correlating with CD8+ IFN-γ-producing cells in the lung but not with those in the spleen. Intranasal immunization was more effective at inducing CD8+ T cell immunity in the lung, and protection, than i.m. immunization. Addition of CpG ODN increased the CD8+ response but not the Ab response. Depletion of CD4 T cells before vaccination with MVA significantly diminished protection against pathogenic WR virus. However, CpG ODN delivered with MVA was able to substitute for CD4 help and protected CD4-depleted mice against WR vaccinia challenge. This study demonstrates for the first time a protective adjuvant effect of CpG ODN for a live viral vector vaccine that may overcome CD4 deficiency in the induction of protective CD8+ T cell-mediated immunity.
Mucosal Administration of Ag85B-ESAT-6 Protects against Infection withMycobacterium tuberculosisand Boosts Prior Bacillus Calmette-Guérin Immunity
Authors: Dietrich Jes , Andersen Claire , Rappuoli Rino , Doherty T. Mark , Jensen Charlotte Green , Andersen Peter 
Published: April 2014

AbstractWe have examined the intranasal administration of a vaccine against Mycobacterium tuberculosis (M.tb) consisting of the mucosal adjuvant LTK63 and the Ag Ag85B-ESAT-6. Vaccination with LTK63/Ag85B-ESAT-6 gave a strong and sustained Th1 response mediated by IFN-γ-secreting CD4 cells, which led to long-lasting protection against tuberculosis, equivalent to that observed with bacillus Calmette-Guérin (BCG) or Ag85B-ESAT-6 in dimethyldioctadecylammonium bromide/monophosphoryl lipid A. Because a crucial element of novel vaccine strategies is the ability to boost BCG-derived immunity, we also tested whether LTK63/Ag85B-ESAT-6 could act as a BCG booster vaccine in BCG-vaccinated mice. We found that vaccinating with LTK63/Ag85B-ESAT-6 strongly boosted prior BCG-stimulated immunity. Compared with BCG-vaccinated nonboosted mice, we observed that infection with M.tb led to a significant increase in anti-M.tb-specific CD4 T cells in the lungs of LTK63/Ag85B-ESAT-6-boosted animals. This correlated with a significant increase in the protection against M.tb in LTK63/Ag85B-ESAT-6-boosted mice, compared with BCG-vaccinated animals. Thus, LTK63/Ag85B-ESAT-6 represents an efficient preventive vaccine against tuberculosis with a strong ability to boost prior BCG immunity.
Antigen-Specific CD8+ T Cells and the Development of Central Memory during Mycobacterium tuberculosis Infection
Authors: Kamath Arati , Woodworth Joshua S.M. , Behar Samuel M. 
Published: April 2014

Abstract
Whether true memory T cells develop in the face of chronic infection such as tuberculosis remains controversial. To address this question, we studied CD8+ T cells specific for the Mycobacterium tuberculosis ESAT6-related Ags TB10.3 and TB10.4. The shared epitope TB10.3/10.420–28 is presented by H-2 Kd, and 20–30% of the CD8+ T cells in the lungs of chronically infected mice are specific for this Ag following respiratory infection with M. tuberculosis. These TB10.3/10.420–28-specific CD8+ T cells produce IFN-γ and TNF and express CD107 on their cell surface, which indicates their likely role as CTL in vivo. Nearly all of the Ag-specific CD8+ T cells in the lungs of chronically infected mice had a T effector cell phenotype based on their low expression of CD62L and CD45RB. In contrast, a population of TB10.3/10.420–28-specific CD8+ T cells was identified in the lymphoid organs that express high levels of CD62L and CD45RB. Antibiotic treatment to resolve the infection led to a contraction of the Ag-specific CD8+ T cell population and was accompanied by an increase in the proportion of CD8+ T cells with a central memory phenotype. Finally, challenge of memory-immune mice with M. tuberculosis was accompanied by significant expansion of TB10.3/10.420–28-specific CD8+ T cells, which suggests that these cells are in fact functional memory T cells.
Engagement of CD14 Mediates the Inflammatory Potential of Monosodium Urate Crystals
Authors: Scott Peter , Ma Hong , Viriyakosol Suganya , Terkeltaub Robert , Liu-Bryan Ru 
Published: April 2014

AbstractPhagocyte ingestion of monosodium urate (MSU) crystals can induce proinflammatory responses and trigger acute gouty inflammation. Alternatively, the uptake of MSU crystals by mature macrophages can be noninflammatory and promote resolution of gouty inflammation. Macrophage activation by extracellular MSU crystals involves apparent recognition and ingestion mediated by TLR2 and TLR4, with subsequent intracellular recognition linked to caspase-1 activation and IL-1β processing driven by the NACHT-LRR-PYD-containing protein-3 inflammasome. In this study, we examined the potential role in gouty inflammation of CD14, a phagocyte-expressed pattern recognition receptor that functionally interacts with both TLR2 and TLR4. MSU crystals, but not latex beads, directly bound recombinant soluble (s) CD14 in vitro. CD14−/− bone marrow-derived macrophages (BMDMs) demonstrated unimpaired phagocytosis of MSU crystals but reduced p38 phosphorylation and ∼90% less IL-1β and CXCL1 release. Attenuated MSU crystal-induced IL-1β release in CD14−/− BMDMs was mediated by decreased pro-IL-1β protein expression and additionally by decreased caspase-1 activation and IL-1β processing consistent with diminished NACHT-LRR-PYD-containing protein-3 inflammasome activation. Coating of MSU crystals with sCD14, but not sTLR2 or sTLR4, restored IL-1β and CXCL1 production in CD14−/− BMDMs in vitro. Gain of function of CD14 directly enhanced TLR4-mediated signaling in response to MSU crystals in transfected Chinese hamster ovary cells in vitro. Last, MSU crystal-induced leukocyte influx at 6 h was reduced by∼75%, and local induction of IL-1β decreased by &gt;80% in CD14−/− mouse s.c. air pouches in vivo. We conclude that engagement of CD14 is a central determinant of the inflammatory potential of MSU crystals.
Vav Proteins in Neutrophils Are Required for FcγR-Mediated Signaling to Rac GTPases and Nicotinamide Adenine Dinucleotide Phosphate Oxidase Component p40(phox)
Authors: Utomo Ahmad , Cullere Xavier , Glogauer Michael , Swat Wojciech , Mayadas Tanya N. 
Published: April 2014

AbstractPhagocytes generate reactive oxygen species, the regulation of which is important in eliminating ingested microbes while limiting tissue damage. Clustering of FcγRs results in the activation of Vav proteins, Rho/Rac guanine nucleotide exchange factors, and results in robust superoxide generation through the NADPH oxidase. In this study, studies in neutrophils isolated from mice deficient in Vav or Rac isoforms demonstrate a critical role for Vav3 in Rac2-dependent activation of the NADPH oxidase following FcγR clustering. However, studies in cytokine-primed cells revealed a strict requirement for Vav1 and Vav3 and Rac1 and Rac2 in the FcγR-mediated oxidative burst. In comparison, Vav was not essential for PMA or G protein-coupled receptor-mediated superoxide generation. The FcγR-mediated oxidative burst defect in Vav-deficient cells was linked to aberrant Rac activation as well as Rac- and actin-polymerization-independent, but PI3K-dependent, phosphorylation of the NADPH oxidase component p40(phox). In macrophages, Vav regulation of Rac GTPases was required specifically in FcγR-mediated activation of the oxidative burst, but not in phagocytosis. Thus, Vav proteins specifically couple FcγR signaling to NADPH oxidase function through a Rac-dependent as well as an unexpected Rac-independent signal that is proximal to NADPH oxidase activation and does not require actin polymerization.
Evidence against Calcium as a Mediator of Mitochondrial Dysfunction during Apoptosis Induced by Arachidonic Acid and Other Free Fatty Acids
Authors: Maia Rita C. , Culver Carolyn A. , Laster Scott M. 
Published: April 2014

AbstractApoptosis is often accompanied by activation of phospholipase A2, causing release of free fatty acids (FFAs), which in turn are thought to contribute to the loss of mitochondrial transmembrane potential (Δψm). In these experiments, we asked whether calcium plays a role as an intermediate in this process. A total of 14 FFAs were compared for their ability to cause loss of Δψm and for their ability to affect levels of intracellular calcium. Among the FFAs, unsaturated FFAs tended to induce apoptosis while saturated FFAs did not. Arachidonic acid (AA) was most damaging, causing loss of Δψm and cell death in 8–10 h while linoleic acid, γ-linolenic acid, and docosapentaenoic also strongly induced apoptosis. Effects of the FFAs on levels of intracellular calcium were very different. Many caused strong calcium responses; however, the ability to induce a strong calcium response was not predictive of ability to induce apoptosis, and overall, we did not find a correlation between apoptosis and calcium induction. Also, verapamil and TMB-8 were able to block the calcium response, but these inhibitors did not prevent loss of Δψm, indicating that the calcium response is not necessary for FFA-induced loss of Δψm. In contrast, we found that cyclosporine A could inhibit the AA-induced loss of Δψm with both whole cells and isolated mitochondria, confirming that the antimitochondrial effects of FFA can stem from direct effects on the mitochondrial permeability transition pore. Finally, we show that the strong apoptosis-inducing activity of AA may stem from its ability to selectively induce its own release.
HIV and Other Lentiviral Infections Cause Defects in Neutrophil Chemotaxis, Recruitment, and Cell Structure: Immunorestorative Effects of Granulocyte-Macrophage Colony-Stimulating Factor
Authors: Heit Bryan , Jones Gareth , Knight Derrice , Antony Joseph M. , Gill M. John , Brown Christopher , Power Christopher , Kubes Paul 
Published: April 2014

Abstract
Patients with HIV infection exhibit deficits in bacterial and fungal clearance, and possibly depressed innate immunity. In this study, we observed that neutrophils from HIV-infected patients have a profound defect in chemotaxis in response to endogenous (IL-8) and bacterial (fMLP) chemoattractants, which was directly correlated with peripheral CD4+ lymphocyte levels but not plasma viral load. A similar chemotactic defect was observed in the feline immunodeficiency virus (FIV) model of HIV infection. Intravital microscopy of FIV-infected animals revealed marked impairment in the in vivo recruitment of leukocytes; specifically integrin-dependent neutrophil adhesion and emigration induced by bacterial products. Treatment of FIV-infected animals with GM-CSF re-established both neutrophil recruitment (rolling, adhesion, and emigration) and in vitro chemotaxis to the levels seen in uninfected animals. This restoration of neutrophil responses was not due to GM-CSF-mediated priming. Rather, HIV and FIV infections resulted in defective neutrophil development, with an ensuing reduction in neutrophil granularity and chemotactic receptor expression. GM-CSF therapy restored neutrophil granularity, implying restoration of normal neutrophil development. Together, our findings underscore the fundamental defects in innate immunity caused by lentivirus infections, while also indicating that GM-CSF may be a potential immunorestorative therapy for HIV-infected patients.