bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tat-Induced FOXO3a Is a Key Mediator of Apoptosis in HIV-1-Infected Human CD4+ T Lymphocytes
Authors: Dabrowska Alicja , Kim Nayoung , Aldovini Anna 
Published: April 2014

Abstract
The high mutation rate of HIV is linked to the generation of viruses expressing proteins with altered function whose impact on disease progression is unknown. We investigated how HIV-1 viruses lacking Env, Vpr, and Nef affect CD4+ T cell survival. We found that in the absence of these proteins, HIV-1-infected CD4+ primary T cells progress to the G0 phase of the cell cycle and to cell death, indicating that viruses expressing inactive forms of these proteins can contribute to the CD4+ T cell decline as the wild-type virus, suggesting that other HIV proteins are responsible for inducing apoptosis. Apoptosis in these cells is triggered by the alteration of the Egr1-PTEN-Akt (early growth response-1/phosphate and tensin homolog deleted on chromosome 10/Akt) and p53 pathways, which converge on the FOXO3a (Forkhead box transcription factor O class 3a) transcriptional activator. The FOXO3a target genes Fas ligand and TRAIL, involved in the extrinsic apoptotic pathway, and PUMA, Noxa, and Bim, which are part of the intrinsic apoptotic pathway, were also up-regulated, indicating that HIV infection leads to apoptosis by the engagement of multiple apoptotic pathways. RNAi-mediated knockdown of Egr1 and FOXO3a resulted in reduced apoptosis in HIV-infected HeLa and CD4+ T cells, providing further evidence for their critical role in HIV-induced apoptosis and G0 arrest. We tested the possibility that Tat is responsible for the T cell apoptosis observed with these mutant viruses. The induction of Egr1 and FOXO3a and its target genes was observed in Jurkat cells transduced by Tat alone. Tat-dependent activation of the Egr1-PTEN-FOXO3a pathway provides a mechanism for HIV-1-associated CD4+ T cell death.
Dendritic Cells Modulate Lung Response toPseudomonas aeruginosain a Murine Model of Sepsis-Induced Immune Dysfunction
Authors: Pène Frédéric , Zuber Benjamin , Courtine Emilie , Rousseau Christophe , Ouaaz Fatah , Toubiana Julie , Tazi Asmaa , Mira Jean-Paul , Chiche Jean-Daniel 
Published: April 2014

AbstractHost infection by pathogens triggers an innate immune response leading to a systemic inflammatory response, often followed by an immune dysfunction which can favor the emergence of secondary infections. Dendritic cells (DCs) link innate and adaptive immunity and may be centrally involved in the regulation of sepsis-induced immune dysfunction. We assessed the contribution of DCs to lung defense in a murine model of sublethal polymicrobial sepsis (cecal ligature and puncture, CLP). In this model, bone marrow-derived DCs (BMDCs) retained an immature phenotype, associated with decreased capacity of IL-12p70 release and impaired priming of T cell lymphocytes. Eight days after CLP surgery, we induced a secondary pulmonary infection through intratracheal instillation of 5 × 106 CFUs of Pseudomonas aeruginosa. Whereas all sham-operated mice survived, 80% of post-CLP mice died after secondary pneumonia. Post-CLP mice exhibited marked lung damage with early recruitment of neutrophils, cytokine imbalance with decreased IL-12p70 production, and increased IL-10 release, but no defective bacterial lung clearance, while systemic bacterial dissemination was almost constant. Concomitant intrapulmonary administration of exogenous BMDCs into post-CLP mice challenged with P. aeruginosa dramatically improved survival. BMDCs did not improve bacterial lung clearance, but delayed neutrophil recruitment, strongly attenuated the early peak of TNF-α and restored an adequate Il-12p70/IL-10 balance in post-CLP mice. Thus, adoptive transfer of BMDCs reversed sepsis-induced immune dysfunction in a relevant model of secondary P. aeruginosa pneumonia. Unexpectedly, the mechanism of action of BMDCs did not involve enhanced antibacterial activity, but occurred by dampening the pulmonary inflammatory response.
Leukotrienes Are Potent Adjuvant during Fungal Infection: Effects on Memory T Cells
Authors: Medeiros Alexandra I. , Sá-Nunes Anderson , Turato Walter M. , Secatto Adriana , Frantz Fabiani G. , Sorgi Carlos A. , Serezani Carlos H. , Deepe George S. , Faccioli Lúcia H. 
Published: April 2014

AbstractLeukotrienes (LTs) are potent lipid mediators involved in the control of host defense. LTB4 induces leukocyte accumulation, enhances phagocytosis and bacterial clearance, and increases NO synthesis. LTB4 is also important in early effector T cell recruitment that is mediated by LTB4 receptor 1, the high-affinity receptor for LTB4. The aims of this study were to evaluate whether LTs are involved in the secondary immune response to vaccination in a murine model of Histoplasma capsulatum infection. Our results demonstrate that protection of wild-type mice immunized with cell-free Ags from H. capsulatum against histoplasmosis was associated with increased LTB4 and IFN-γ production as well as recruitment of memory T cells into the lungs. In contrast, cell-free Ag-immunized mice lacking 5-lipoxygenase−/−, a critical enzyme involved in LT synthesis, displayed a marked decrease on recruitment of memory T cells to the lungs associated with increased synthesis of TGF-β as well as IL-10. Strikingly, these effects were associated with increased mortality to 5-lipoxygenase−/−-infected mice. These data establish an important immunomodulatory role of LTs, in both the primary and secondary immune responses to histoplasmosis.
Vaccination with LivePlasmodium yoeliiBlood Stage Parasites under Chloroquine Cover Induces Cross-Stage Immunity against Malaria Liver Stage
Authors: Belnoue Elodie , Voza Tatiana , Costa Fabio T. M. , Grüner Anne Charlotte , Mauduit Marjorie , Rosa Daniela Santoro , Depinay Nadya , Kayibanda Michèle , Vigário Ana Margarida , Mazier Dominique , Snounou Georges , Sinnis Photini , Rénia Laurent 
Published: April 2014

AbstractImmunity to malaria has long been thought to be stage-specific. In this study we show that immunization of BALB/c mice with live erythrocytes infected with nonlethal strains of Plasmodium yoelii under curative chloroquine cover conferred protection not only against challenge by blood stage parasites but also against sporozoite challenge. This cross-stage protection was dose-dependent and long lasting. CD4+ and CD8+ T cells inhibited malaria liver but not blood stage. Their effect was mediated partially by IFN-γ, and was completely dependent of NO. Abs against both pre-erythrocytic and blood parasites were elicited and were essential for protection against blood stage and liver stage parasites. Our results suggest that Ags shared by liver and blood stage parasites can be the foundation for a malaria vaccine that would provide effective protection against both pre-erythrocytic and erythrocytic asexual parasites found in the mammalian host.
IL-12 Produced by Dendritic Cells Augments CD8+ T Cell Activation through the Production of the Chemokines CCL1 and CCL17
Authors: Henry Curtis J. , Ornelles David A. , Mitchell Latoya M. , Brzoza-Lewis Kristina L. , Hiltbold Elizabeth M. 
Published: April 2014

AbstractIL-12 family members are an important link between innate and adaptive immunity. IL-12 drives Th1 responses by augmenting IFN-γ production, which is key for clearance of intracellular pathogens. IL-23 promotes the development of IL-17-producing CD4+ T cells that participate in the control of extracellular pathogens and the induction of autoimmunity. However, recent studies have shown that these cytokines can modulate lymphocyte migration and cellular interactions. Therefore, we sought to determine the individual roles of IL-12 and IL-23 in naive CD8+ T cell activation by addressing their ability to influence IFN-γ production and cellular interaction dynamics during priming by Listeria monocytogenes-infected dendritic cells (DC). We found that IL-12 was the major cytokine influencing the level of IFN-γ production by CD8+ T cells while IL-23 had little effect on this response. In addition, we observed that IL-12 promoted longer duration conjugation events between CD8+ T cells and DC. This enhanced cognate interaction time correlated with increased production of the chemokines CCL1 and CCL17 by WT but not IL-12-deficient DC. Neutralization of both chemokines resulted in reduced interaction time and IFN-γ production, demonstrating their importance in priming naive CD8+ T cells. Our study demonstrates a novel mechanism through which IL-12 augments naive CD8+ T cell activation by facilitating chemokine production, thus promoting more stable cognate interactions during priming.
Mycobacterium tuberculosis-Specific CD8+ T Cells Require Perforin to Kill Target Cells and Provide Protection In Vivo
Authors: Woodworth Joshua S. , Wu Ying , Behar Samuel M. 
Published: April 2014

AbstractOptimal immunity to Mycobacterium tuberculosis (Mtb) infection requires CD8+ T cells, and several current Mtb vaccine candidates are being engineered to elicit enhanced CD8+ T cell responses. However, the function of these T cells and the mechanism by which they provide protection is still unknown. We have previously shown that CD8+ T cells specific for the mycobacterial Ags CFP10 and TB10.4 accumulate in the lungs of mice following Mtb infection and have cytolytic activity in vivo. In this study, we determine which cytolytic pathways are used by these CD8+ T cells during Mtb infection. We find that Mtb-specific CD8+ T cells lacking perforin have reduced cytolytic capacity in vivo. In the absence of perforin, the residual cytolytic activity is CD95 and TNFR dependent. This is particularly true in Mtb-infected lung tissue where disruption of both perforin and CD95 eliminates target cell lysis. Moreover, adoptive transfer of immune CD8+ T cells isolated from wild-type, but not perforin-deficient mice, protect recipient mice from Mtb infection. We conclude that CD8+ T cells elicited following Mtb infection use several cytolytic pathways in a hierarchical and compensatory manner dominated by perforin-mediated cytolysis. Finally, although several cytolytic pathways are available, adoptively transferred Mtb-specific CD8+ T cells require perforin-mediated cytolysis to protect animals from infection. These data show that CD8+ T cell-mediated protection during Mtb infection requires more than the secretion of IFN-γ and specifically defines the CD8+ cytolytic mechanisms utilized and required in vivo.
Early Divergence in Neutrophil Apoptosis between Pathogenic and Nonpathogenic Simian Immunodeficiency Virus Infections of Nonhuman Primates
Authors: Elbim Carole , Monceaux Valerie , Mueller Yvonne M. , Lewis Mark G. , François Stephanie , Diop Ousmane , Akarid Khadija , Hurtrel Bruno , Gougerot-Pocidalo Marie-Anne , Lévy Yves , Katsikis Peter D. , Estaquier Jerome 
Published: April 2014

Abstract
We used pathogenic and nonpathogenic simian models of SIV infection of Chinese and Indian rhesus macaque (RMs) and African green monkeys (AGMs), respectively, to investigate the relationship between polymorphonuclear neutrophil (PMN) death and the extent of viral replication and disease outcome. In this study, we showed that PMN death increased early during the acute phase of SIV infection in Chinese RMs and coincided with the peak of viral replication on day 14. The level of PMN death was significantly more severe in RMs that progressed more rapidly to AIDS and coincided with neutropenia. Neutropenia was also observed in Indian RMs and was higher in non-Mamu-A*01 compared with Mamu-A*01 animals. In stark contrast, no changes in the levels of PMN death were observed in the nonpathogenic model of SIVagm-sab (sabaeus) infection of AGMs despite similarly high viral replication. PMN death was a Bax and Bak-independent mitochondrial insult, which is prevented by inhibiting calpain activation but not caspases. We found that BOB/GPR15, a SIV coreceptor, is expressed on the PMN surface of RMs at a much higher levels than AGMs and its ligation induced PMN death, suggesting that SIV particle binding to the cell surface is sufficient to induce PMN death. Taken together, our results suggest that species-specific differences in BOB/GPR15 receptor expression on PMN can lead to increased acute phase PMN death. This may account for the decline in PMN numbers that occurs during primary SIV infection in pathogenic SIV infection and may have important implications for subsequent viral replication and disease progression.
Factor H Binding as a Complement Evasion Mechanism for an Anaerobic Pathogen, Fusobacterium necrophorum
Authors: Friberg Nathalie , Carlson Petteri , Kentala Erna , Mattila Petri S. , Kuusela Pentti , Meri Seppo , Jarva Hanna 
Published: April 2014

Abstract
Fusobacterium necrophorum subspecies funduliforme is an obligate anaerobic Gram-negative rod causing invasive infections such as the life-threatening Lemierre’s syndrome (sore throat, septicemia, jugular vein thrombosis, and disseminated infection). The aim of our study was to understand if and how F. necrophorum avoids C activation. We studied 12 F. necrophorum subsp. funduliforme strains isolated from patients with sepsis. All strains were resistant to serum killing after a 1-h incubation in 20% serum. The bacteria bound, at different levels, the C inhibitor factor H (fH). Binding was ionic and specific in nature and occurred via sites on both the N terminus and the C terminus of fH. Bound fH remained functionally active as a cofactor for factor I in the cleavage of C3b. Interestingly, patients with the most severe symptoms carried strains with the strongest ability to bind fH. An increased C3b deposition and membrane attack complex formation on the surface of a weakly fH-binding strain was observed and its survival in serum at 3.5 h was impaired. This strain had not caused a typical Lemierre’s syndrome. These data, and the fact that fH-binding correlated with the severity of disease, suggest that the binding of fH contributes to virulence and survival of F. necrophorum subsp. funduliforme in the human host. Our data show, for the first time, that an anaerobic bacterium is able to bind the C inhibitor fH to evade C attack.
The 15-Deoxy-Δ12,14-Prostaglandin J2 Suppresses Monocyte Chemoattractant Protein-1 Expression in IFN-γ-Stimulated Astrocytes through Induction of MAPK Phosphatase-1
Authors: Lee Jee Hoon , Woo Joo Hong , Woo Sang Uk , Kim Kwang Soo , Park Sang Myun , Joe Eun-hye , Jou Ilo 
Published: April 2014

AbstractThe 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) is a cyclopentene PG generated from PGD2. It is an endogenous ligand of the peroxisome proliferator-activated receptor-γ that is primarily involved in adipocyte differentiation and lipid metabolism. Its anti-inflammatory actions have recently attracted considerable research attention, although the precise role and underlying mechanisms of these actions are largely unknown. In the present study, we focused on the inhibitory action of 15d-PGJ2 on the chemokine MCP-1, which plays a key role in the initiation and progression of inflammation by recruiting inflammatory cells to lesion sites. We found that 15d-PGJ2 suppressed MCP-1 transcription and protein secretion in IFN-γ-stimulated brain astrocytes. The inhibitory effects of 15d-PGJ2 on MCP-1 resulted from its actions on the transcription factors, AP-1 and specificity protein-1, which play key roles in IFN-γ-induced MCP-1 expression in astrocytes. Of interest, the negative effects of 15d-PGJ2 on AP-1/specificity protein-1 signaling and the resulting inhibition of MCP-1 expression were mediated by MAPK phosphatase (MKP)-1 activity, which was induced by 15d-PGJ2 in a peroxisome proliferator-activated receptor-independent manner. Thus, our data demonstrate a novel anti-inflammatory mechanism of 15d-PGJ2 involving MKP-1. Considering the importance of MCP-1 in inflammatory processes, our results suggest that 15d-PGJ2 analogues may have therapeutic potential to attenuate inflammatory brain diseases by inducing MKP-1 expression.
Antagonism of Airway Tolerance by Endotoxin/Lipopolysaccharide through Promoting OX40L and Suppressing Antigen-Specific Foxp3+ T Regulatory Cells
Authors: Duan Wei , So Takanori , Croft Michael 
Published: April 2014

Abstract
Respiratory exposure to allergens can lead to airway tolerance. Factors that antagonize tolerance mechanisms in the lung might result in susceptibility to diseases such as asthma. We show that inhalation of endotoxin/LPS with Ag prevented airway tolerance and abolished protection from T cell-driven asthmatic lung inflammation. Under conditions leading to tolerance, adaptive Ag-specific CD4+Foxp3+ T regulatory cells (Treg) were generated following exposure to intranasal Ag and outnumbered IL-4- and IFN-γ-producing CD4 T cells by 100:1 or greater. Inhaled LPS altered the ratio of Treg to IL-4+ or IFN-γ+ T cells by concomitantly suppressing Treg generation and promoting effector T cell generation. LPS induced OX40L expression on dendritic cells and B cells that resulted in a synergistic activity between TLR4 and OX40 signals, leading to production of IL-4, IFN-γ, and IL-6, which blocked Treg development. Furthermore, inhibiting OX40/OX40L interactions prevented LPS from suppressing tolerance, and resulted in the generation of greater numbers of adaptive Treg. Thus, cooperation between TLR4 and OX40 controls susceptibility to developing airway disease via modulating the balance between adaptive Treg and IL-4+ or IFN-γ+ T cells. Targeting OX40L then has the potential to improve the efficacy of Ag immunotherapy to promote tolerance.
Transmigration of Neutrophils across Inflamed Endothelium Is Signaled through LFA-1 and Src Family Kinase
Authors: Sarantos Melissa R. , Zhang Hong , Schaff Ulrich Y. , Dixit Neha , Hayenga Heather N. , Lowell Clifford A. , Simon Scott I. 
Published: April 2014

AbstractLeukocyte capture on inflamed endothelium is facilitated by a shift in LFA-1 from low to high affinity that supports binding to ICAM-1. LFA-1 bonds help anchor polymorphonuclear leukocytes (PMN) to inflamed endothelium in shear flow, and their redistribution to the leading edge guides pseudopod formation, migration, and extravasation. These events can be disrupted at the plasma membrane by stabilizing LFA-1 in a low- or intermediate-affinity state with allosteric small molecules. We hypothesized that a minimum dimeric bond formation between high-affinity LFA-1 and ICAM-1 under shear stress is necessary to catalyze transmembrane signaling of directed cell migration. Microspheres and substrates were derivatized with monomeric or dimeric ICAM-1 to simulate the surface of inflamed endothelium under defined ligand valence. Binding to dimeric ICAM-1, and not monomeric ICAM-1, was sufficient to elicit assembly of F-actin and phosphorylation of Src family kinases that colocalized with LFA-1 on adherent PMN. Genetic deletion or small molecule inhibition of Src family kinases disrupted their association with LFA-1 that correlated with diminished polarization of arrested PMN and abrogation of transmigration on inflamed endothelium. We conclude that dimeric bond clusters of LFA-1/ICAM-1 provide a key outside-in signal for orienting cytoskeletal dynamics that direct PMN extravasation at sites of inflammation.
Chemokine Receptor CCR1 Regulates Inflammatory Cell Infiltration after Renal Ischemia-Reperfusion Injury
Authors: Furuichi Kengo , Gao Ji-Liang , Horuk Richard , Wada Takashi , Kaneko Shuichi , Murphy Philip M. 
Published: April 2014

Abstract
Neutrophils and macrophages rapidly infiltrate the kidney after renal ischemia-reperfusion injury, however specific molecular recruitment mechanisms have not been fully delineated for these cell types. Here we provide genetic and pharmacologic evidence supporting a positive role for the chemokine receptor CCR1 in macrophage and neutrophil infiltration in a 7 day mouse model of renal ischemia-reperfusion injury. By day 7, injured kidneys from mice lacking CCR1 contained 35% fewer neutrophils and 45% fewer macrophages than injured kidneys from wild-type control mice. Pretreatment of wild-type mice with the specific CCR1 antagonist BX471 also suppressed neutrophil and macrophage infiltration in the model. Injured kidneys from mice lacking CCR1 also had reduced content of the CCR1 ligands CCL3 (MIP-1α) and CCL5 (RANTES) compared with injured kidneys from wild-type controls, suggesting a leukocyte source for these inflammatory chemokines and existence of a CCR1-dependent positive feedback loop for leukocyte infiltration in the model. Local leukocyte proliferation and apoptosis were detected after injury, but were not dependent on CCR1. Also, the extent of necrotic and fibrotic damage and decline in renal function in injured kidneys was similar in wild-type and CCR1-deficient mice. Thus, CCR1 appears to regulate trafficking of macrophages and neutrophils to kidney in a mouse model of renal ischemia-reperfusion injury, however this activity does not appear to affect tissue injury.
T-bet and Eomesodermin Play Critical Roles in Directing T Cell Differentiation to Th1 versus Th17
Authors: Yang Yu , Xu Jiangnan , Niu Yanyan , Bromberg Jonathan S. , Ding Yaozhong 
Published: April 2014

AbstractTh1 and Th17 cells are crucial in immune regulation and autoimmune disease development. By adding Stat6 deficiency to T-bet deficiency, and thus negating effects from elevated levels of IL-4/Stat6/GATA3 Th2 signals in T-bet-deficient cells, we investigated the signals important for Th1 and Th17 cell differentiation and their role in colitis development. The data reveal that Eomesodermin compensates T-bet deficiency for IFN-γ and Th1 development. However, without T-bet, IFN-γ production and Th1 differentiation are susceptible to inhibition by IL-6 and TGFβ. As a result, Th17 development is strongly favored, the threshold for TGFβ requirement is lowered, and IL-6 drives Th17 differentiation, elucidating a critical role for T-bet in directing T cell differentiation to Th1 vs Th17. In contrast to IL-6 plus TGFβ-driven Th17, IL-6-driven Th17 cells do not express IL-10 and they induce a more intense colitis. Naive CD4 T cells deficient in Stat6 and T-bet also induce a Th17-dominant colitis development in vivo. Our data provide new insights into the choice between Th1 and Th17 development and their roles in autoimmunity.
Alveolar Macrophages from Septic Mice Promote Polymorphonuclear Leukocyte Transendothelial Migration via an Endothelial Cell Src Kinase/NADPH Oxidase Pathway
Authors: Wang Zhanfei , Rui Tao , Yang Min , Valiyeva Fatima , Kvietys Peter R. 
Published: April 2014

Abstract
Alveolar macrophages (AMφ) have been implicated in the polymorphonuclear leukocyte (PMN) recruitment to the lungs during sepsis. Using an in vivo murine model of sepsis (feces in the peritoneum), we show that peritonitis leads to increased activation of AMφ and PMN migration into pulmonary alveoli. To assess cellular mechanisms, an in vitro construct of the pulmonary vascular-interstitial interface (murine AMφ, pulmonary endothelial cells, and PMN) and a chimera approach were used. Using immunologic (Abs) and genetic blockade (CXCR2-deficient AMφ), we show that CXC chemokines in septic plasma are responsible for the activation of AMφ. The activated AMφ can promote PMN transendothelial migration, even against a concentration gradient of septic plasma, by generating platelet-activating factor and H2O2. Platelet-activating factor/H2O2 induce an oxidant stress in the adjacent endothelial cells, an event that appears to be a prerequisite for PMN transendothelial migration, since PMN migration is abrogated across Cu/Zn-superoxide dismutase overexpressing endothelial cells. Using gp91-deficient endothelial cells, we show that NADPH oxidase plays an important role in the AMφ-induced PMN transendothelial migration. Pharmacologic/small interfering RNA blockade of Src kinase inhibits AMφ-induced endothelial NADPH oxidase activation and PMN migration. Collectively, our findings indicate that the PMN transendothelial migration induced by septic AMφ is dependent on the generation of superoxide in endothelial cells via the Src kinase/NADPH oxidase signaling pathway.