bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunosuppression in Hamsters with Progressive Visceral Leishmaniasis Is Associated with an Impairment of Protein Kinase C Activity in Their Lymphocytes That Can Be Partially Reversed by Okadaic Acid or Anti-Transforming Growth Factor β Antibody
Authors: Mookerjee Ananda , Sen Parimal C. , Ghose Asoke C. 
Published: April 2003

ABSTRACTProgressive visceral infection of golden hamsters byLeishmania donovaniamastigotes led to gradual impairment of the proliferative responses of their splenic or peripheral blood mononuclear cells (SPMC or PBMC, respectively) to in vitro stimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin (Io). Removal of macrophage-like adherent cells from SPMC or PBMC of infected animals (I-SPMC or I-PBMC) was earlier shown to restore almost completely their lymphoproliferative responses to PMA plus Io. The present study was directed to evaluate the status of protein kinase C (PKC), a molecule(s) known to play a key role in the lymphoproliferative process. Our results demonstrate that PKC activities (Ca2+, phosphatidyl serine, and diacyl glycerol dependent) in the cytosolic fraction of untreated nonadherent I-SPMC or I-PBMC as well as in the membrane fraction of PMA-treated cells were decreased significantly relative to those for normal controls. However, removal of adherent cells from I-SPMC or I-PBMC and subsequent overnight in vitro cultivation of nonadherent cells (lymphocytes) resulted in significant restoration of PKC activity in the cytosolic or membrane fraction of untreated or PMA-treated cells, respectively. Partial, though significant, restoration of PKC activity could also be achieved in the membrane fraction of PMA-treated cells following overnight in vitro treatment of I-SPMC or I-PBMC with the Ser/Thr phosphatase inhibitor okadaic acid (OA) or an anti-transforming growth factor β (anti-TGF-β) neutralizing antibody. These results correlated well with the ability of OA or the anti-TGF-β antibody to restore the lymphoproliferative response of I-SPMC or I-PBMC following stimulation with PMA plus Io. Interestingly enough, immunoblotting experiments failed to show any reduction in the level or translocation (following PMA treatment) of conventional PKC isoforms in the SPMC or PBMC of infected animals compared to those of normal controls. The results presented in this study suggest that the adherent cells generated in the SPMC or PBMC of infected animals exert a suppressive effect on the proliferative response of nonadherent cells (lymphocytes) which is likely to be mediated through the downregulation of the activation pathway involving PKC and its downstream molecules such as mitogen-activated protein kinases. Further, the observed suppression of PKC activity and subsequent lymphoproliferative responses can be attributed to alternations in the intracellular phosphorylation-dephosphorylation events. The relevance of these results is discussed in relation to the role of TGF-β, levels of which are known to be elevated in visceral leishmaniasis.
Chondroitin Sulfate Proteoglycan Expression and Binding ofPlasmodium falciparum-Infected Erythrocytes in the Human Placenta during Pregnancy
Authors: Agbor-Enoh Sean T. , Achur Rajeshwara N. , Valiyaveettil Manojkumar , Leke Rose , Taylor Diane W. , Gowda D. Channe 
Published: April 2003

ABSTRACTA characteristic feature of malaria during pregnancy is the sequestration ofPlasmodium falciparum-infected red blood cells (IRBCs) in the intervillous spaces of the placenta. We have recently shown that unusually low-sulfated chondroitin sulfate proteoglycans (CSPGs) present in the intervillous spaces mediate the adherence of IRBCs in the placenta. In areas of endemicity, the prevalence ofP. falciparuminfection in pregnant women peaks during weeks 13 to 20 and then gradually declines, implying that the placental CSPGs are available for IRBC adhesion early during the pregnancy. However, there is no information on the expression and composition of CSPGs during pregnancy. In this study, the expression pattern of CSPGs during the course of pregnancy was investigated. The CSPGs were purified from placentas of various gestational ages, characterized, and tested for the ability to bind IRBCs. The data demonstrate that the CSPGs are present in the intervillous spaces throughout the second and third trimesters. The levels of CSPGs expressed per unit tissue weight were similar in placentas of various gestational ages. However, the structures of the intervillous-space CSPGs changed considerably during the course of pregnancy. In particular, the molecular weight was decreased, with an accompanying gradual increase in the CSPG size polydispersity, from 16 weeks until 38 weeks. The sulfate content was increased considerably after 24 weeks. Despite these structural changes, the CSPGs of placentas of various gestational ages efficiently supported the binding of IRBCs. These results demonstrate that CSPGs can mediate the sequestration of IRBCs in the intervillous spaces of the placenta during the entire second and third trimesters and possibly during the later part of the first trimester as well.
Mice Genetically Deficient in Immunoglobulin E Are More Permissive Hosts than Wild-Type Mice to a Primary, but Not Secondary, Infection with the Filarial NematodeBrugia malayi
Authors: Spencer L. A. , Porte P. , Zetoff C. , Rajan T. V. 
Published: April 2003

ABSTRACTPrimary and secondary murine and human infections withBrugia malayiare characterized by substantial increases in levels of immunoglobulin E (IgE). To investigate whether this is necessary for worm clearance, IgE−/−mice were subjected to primary- and secondary-infection protocols. Following a primary infection, IgE−/−mice displayed a profound deficit in their ability to clear an intraperitoneal injection of L3 infective-stage larvae in comparison to wild-type counterparts and maintained substantial worm burdens as late as 10 weeks postinfection. Although viable adult parasites were recovered at this late time point from IgE−/−mice, the majority of the mice remained free of microfilariae. IgE−/−cohorts subjected to a secondary-infection protocol were able to clear the challenge inoculation in an accelerated manner, with kinetics similar to that observed in the wild-type animals. Analysis of the humoral response in IgE−/−mice following infection demonstrates a defect in IgG1 and IgG2a production, in addition to the expected lack of IgE. The IgG1 deficiency is no longer evident following a secondary infection. These data imply that deficiencies other than IgE production (i.e., IgG1 production) deficiency may be responsible for the increased permissiveness of IgE−/−mice as hosts following infection withB. malayi.
Inhibition of Response to Alpha Interferon byMycobacterium tuberculosis
Authors: Prabhakar Savita , Qiao Yaming , Hoshino Yoshihiko , Weiden Michael , Canova Antony , Giacomini Elena , Coccia Eliana , Pine Richard 
Published: April 2003

ABSTRACTWe previously reported that infection byMycobacterium tuberculosis, the causative agent of tuberculosis, leads to secretion of alpha/beta interferon (IFN-α/β). While IFN-α/β ordinarily stimulates formation of signal transducer and stimulator of transcription-1 (STAT-1) homodimers and IFN-stimulated gene factor-3 (ISGF-3), only ISGF-3 is found in infected human monocytes and macrophages. We have now investigated the basis for this unusual profile of transcription factor activation and its consequences for regulation of transcription, as well as the impact of infection on response to IFN-α. After infection, IFN-α stimulation of STAT-1 homodimers is inhibited in monocytes and macrophages, while stimulation of ISGF-3 increases in monocytes but tends to decline in macrophages. Effects of infection on the abundance of ISGF-3 subunits, STAT-1, STAT-2, and interferon regulatory factor 9, and on tyrosine phosphorylation of STAT-1 and STAT-2 explain the observed changes in DNA-binding activity, which correlate with increased or inhibited transcription of genes regulated by ISGF-3 and STAT-1. Infection byMycobacterium bovisBCG does not inhibit IFN-α-stimulated tyrosine phosphorylation of STAT-1, formation of homodimers, or transcription of genes regulated by STAT-1 homodimers, suggesting that inhibition of the response to IFN-α/β byM. tuberculosisis an aspect of pathogenicity. Thus, this well-known feature of infection by pathogenic viruses may also be a strategy employed by pathogenic bacteria.
Role of Innate Immune Factors in the Adjuvant Activity of Monophosphoryl Lipid A
Authors: Martin Michael , Michalek Suzanne M. , Katz Jannet 
Published: April 2003

ABSTRACTMonophosphoryl lipid A (MPL) is a nontoxic derivative of lipopolysaccharide (LPS) that exhibits adjuvant properties similar to those of the parent LPS molecule. However, the mechanism by which MPL initiates its immunostimulatory properties remains unclear. Due to the involvement of Toll-like receptors in recognizing and transducing intracellular signals in response to LPS, the aim of the present study was to determine the ability of MPL to utilize the Toll-like receptor 2 (TLR2) and TLR4. We provide evidence that MPL differentially utilizes TLR2 and TLR4 for the induction of tumor necrosis factor alpha, interleukin 10 (IL-10), and IL-12 by purified human monocytes as well as by human peripheral blood mononuclear cells. Assessment of NF-κB activity demonstrated that MPL utilized TLR2 and especially TLR4 for the activation of NF-κB p65 by human monocytes. In addition, stimulation of human monocytes by MPL led to an up-regulation of the costimulatory molecules CD80 and CD86, an effect that could be reduced by pretreatment of cells with a monoclonal antibody to TLR2 or TLR4. Analysis of MPL-induced activation of the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinases revealed that MPL utilized both TLR2 and TLR4 for the phosphorylation of ERK1/2, while TLR4 was the predominant receptor involved in the ability of MPL to phosphorylate p38. Moreover, using selective inhibitors for MAP kinase kinase (PD98059) and p38 (SB203580), we show that ERK1/2 exhibited differential effects on production of TNF-α and IL-12 p40 by human monocytes, whereas MPL-induced activation of p38 appeared to be predominantly involved in production of IL-10 and IL-12 p40 by MPL-stimulated monocytes. Taken together, these findings aid in understanding the cellular mechanisms by which MPL induces host cell activation and subsequent adjuvant properties.
Staphylococcal Enterotoxin B-Induced Acute Inflammation Is Inhibited by Dexamethasone: Important Role of CXC Chemokines KC and Macrophage Inflammatory Protein 2
Authors: Schramm Rene , Thorlacius Henrik 
Published: April 2003

ABSTRACTThis study was conducted to examine the anti-inflammatory mechanisms of dexamethasone during leukocyte recruitment and expression of the CXC chemokines macrophage inflammatory protein 2 (MIP-2) (CXCL2) and cytokine-induced neutrophil chemoattractant (KC) (CXCL1) in staphylococcal enterotoxin B (SEB)-induced acute inflammation. To do this, SEB was injected into murine air pouches with or without dexamethasone pretreatment for 2 h. SEB induced infiltration of leukocytes in a dose- and time-dependent manner, with the maximal response observed after 4 h of treatment with 10 μg of SEB. The recruited leukocytes comprised more than 77% neutrophils. Moreover, SEB challenge (10 μg) provoked time-dependent secretion of CXC chemokines, which peaked after 1 h. Local administration of antibodies against MIP-2 and KC significantly reduced SEB-triggered neutrophil accumulation by 38 and 59%, respectively. Dexamethasone (10 mg kg−1) significantly decreased neutrophil recruitment by 82% and reduced secretion of MIP-2 and KC by 89 and 85%, respectively, in response to SEB challenge. Our data demonstrate that dexamethasone potently inhibits neutrophil recruitment in SEB-induced inflammation. Moreover, we provide evidence that MIP-2 and KC are key mediators in the neutrophil response to SEB. Furthermore, our findings demonstrate that dexamethasone attenuates SEB-induced expression of MIP-2 and KC. Thus, this study elucidates important signaling pathways of SEB-induced neutrophil recruitment and anti-inflammatory mechanisms of action of dexamethasone.
Cleavage of the Human Immunoglobulin A1 (IgA1) Hinge Region by IgA1 Proteases Requires Structures in the Fc region of IgA
Authors: Chintalacharuvu Koteswara R. , Chuang Philip D. , Dragoman Ashley , Fernandez Christine Z. , Qiu Jiazhou , Plaut Andrew G. , Trinh K. Ryan , Gala Françoise A. , Morrison Sherie L. 
Published: April 2003

ABSTRACTSecretory immunoglobulin A (IgA) protects the mucosal surfaces against inhaled and ingested pathogens. Many pathogenic bacteria produce IgA1 proteases that cleave in the hinge of IgA1, thus separating the Fab region from the Fc region and making IgA ineffective. Here, we show thatHaemophilus influenzaetype 1 andNeisseria gonorrhoeaetype 2 IgA1 proteases cleave the IgA1 hinge in the context of the constant region of IgA1 or IgA2m(1) but not in the context of IgG2. Both Cα2 and Cα3 but not Cα1 are required for the cleavage of the IgA1 hinge byH. influenzaeandN. gonorrhoeaeproteases. While there was no difference in the cleavage kinetics between wild-type IgA1 and IgA1 containing only the first GalNAc residue of the O-linked glycans, the absence of N-linked glycans in the Fc increased the ability of theN. gonorrhoeaeprotease to cleave the IgA1 hinge. Taken together, these results suggest that, in addition to the IgA1 hinge, structures in the Fc region of IgA are required for the recognition and cleavage of IgA1 by theH. influenzaeandN. gonorrhoeaeproteases.
Interleukin-12 p40- and Fas Ligand-Dependent Apoptotic Pathways Involving STAT-1 Phosphorylation Are Triggered during Infection with a Virulent Strain ofToxoplasma gondii
Authors: Gavrilescu L. Cristina , Denkers Eric Y. 
Published: April 2003

ABSTRACTToxoplasma gondiiis an opportunistic intracellular parasite. Infection with the high-virulenceT. gondiistrain RH induces inflammatory cytokine overproduction and uncontrolled apoptosis in lymphoid organs. Here, we show by fluorescent terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay and binding of fluorescein isothiocyanate-conjugated VAD-FMK, an irreversible pan-caspase inhibitor, that parasite-triggered apoptosis occurs among CD4+, CD8+, B220+, Gr-1+, and NK1.1+splenic populations. Caspases 8 and 9 were activated during infection, implicating cell surface death receptors and mitochondria in apoptosis. Induction of apoptosis was absent among all cell populations in both interleukin-12 (IL-12) p40- and Fas ligand (FasL)-negative mice. STAT-1 phosphorylation correlated with onset of apoptosis during infection, but in the absence of IL-12 p40 and functional FasL, activation of this transcription factor failed to occur. The results demonstrateT. gondii-induced activation of multiple apoptotic pathways, dependent upon both IL-12 p40 and FasL, that may play a role in the lethal pathology of infection.
Changes in Pulmonary Function and Parasite Burden in Rats Infected with
Strongyloides venezuelensis
Concomitant with Induction of Allergic Airway Inflammation
Authors: Negrão-Corrêa Deborah , Silveira Micheline R. , Borges Cynthia M. , Souza Danielle G. , Teixeira Mauro M. 
Published: April 2003

ABSTRACT

The prevalence of allergic diseases such as asthma has increased markedly over the past few decades. To evaluate the possible mutual influence of helminth infection and allergy, the combined effects of experimental allergic airway inflammation and infection with
Strongyloides venezuelensis
on various parasitological and inflammatory indices were evaluated in the rat. A challenge of immunized rats with aerosolized ovalbumin (OVA) resulted in eosinophilic inflammation that peaked 48 h after the challenge and was accompanied by airway hyperresponsiveness (AHR) to an intravenous acetylcholine challenge.
S. venezuelensis
infection concomitant with an OVA challenge of immunized rats resulted in prolonged pulmonary inflammation with increased eosinophil infiltration in bronchoalveolar lavage fluid but not in the lung tissue. These rats also showed a significant parasite burden reduction, especially during parasite migration through the lungs. However, the fecundity rates of worms that reached the intestine were similar in allergic and nonallergic animals. Despite airway inflammation, the increased responsiveness of the airways in the experimental asthma model was suppressed during parasite migration through the lungs (2 days). In contrast, parasite-induced AHR was unchanged 5 days after infection in immunized and challenged rats. In conclusion, infection with
S. venezuelensis
interfered with the onset of AHR following an antigen challenge of immunized rats. The ability of parasites to switch off functional airway responses is therapeutically relevant because we may learn from parasites how to modulate lung function and, hence, the AHR characteristic of asthmatic patients.
Gene Expression Profiling of
Helicobacter pylori
Reveals a Growth-Phase-Dependent Switch in Virulence Gene Expression
Authors: Thompson Lucinda J. , Merrell D. Scott , Neilan Brett A. , Mitchell Hazel , Lee Adrian , Falkow Stanley 
Published: April 2003

ABSTRACT

The global pattern of growth-phase-dependent gene expression of
Helicobacter pylori
during in vitro culture was analyzed by using a high-density DNA microarray. To detect consistent coordinated gene expression in this bacterium, temporal changes in transcription were assessed in two independent time courses. Cluster analysis of the expression profiles highlighted a major switch in gene expression during the late log-to-stationary phase transition that we have termed the Log-Stat switch. Statistical analysis of the genes that were significantly induced or repressed during the Log-Stat switch revealed that many of these genes were related to virulence. Among these, expression of the genes for the neutrophil activating protein (
napA
) and the major flagellin subunit (
flaA
) were significantly induced. Additionally, the expression of a number of genes involved in iron homeostasis changed dramatically at this switch; the gene for the iron-storage protein,
pfr
, was induced, while the genes for two putative iron uptake proteins,
fecA
and
frpB
, were significantly repressed. These data suggest that the late log phase may correspond to the most virulent phase of growth in
H. pylori
and may be intimately related to its pathogenesis. The use of microarrays to analyze the kinetics of the transcriptional response of a bacterial pathogen to a changing environment has enabled the discovery of previously unappreciated relationships between genes by elucidation of coordinated gene expression profiles.
MtsABC Is Important for Manganese and Iron Transport, Oxidative Stress Resistance, and Virulence of
Streptococcus pyogenes
Authors: Janulczyk Robert , Ricci Susanna , Björck Lars 
Published: April 2003

ABSTRACT

MtsABC is a
Streptococcus pyogenes
ABC transporter which was previously shown to be involved in iron and zinc accumulation. In this study, we showed that an
mtsABC
mutant has impaired growth, particularly in a metal-depleted medium and an aerobic environment. In metal-depleted medium, growth was restored by the addition of 10 μM MnCl
2
, whereas other metals had modest or no effect. A characterization of metal radioisotope accumulation showed that manganese competes with iron accumulation in a dose-dependent manner. Conversely, iron competes with manganese accumulation but to a lesser extent. The mutant showed a pronounced reduction (>90%) of
54
Mn accumulation, showing that MtsABC is also involved in Mn transport. Using paraquat and hydrogen peroxide to induce oxidative stress, we show that the mutant has an increased susceptibility to reactive oxygen species. Moreover, activity of the manganese-cofactored superoxide dismutase in the mutant is reduced, probably as a consequence of reduced intracellular availability of manganese. The enzyme functionality was restored by manganese supplementation during growth. The mutant was also attenuated in virulence, as shown in animal experiments. These results emphasize the role of MtsABC and trace metals, especially manganese, for
S. pyogenes
growth, susceptibility to oxidative stress, and virulence.
Amastigote Load and Cell Surface Phenotype of Infected Cells from Lesions and Lymph Nodes of Susceptible and Resistant Mice Infected withLeishmania major
Authors: Muraille Eric , De Trez Carl , Pajak Bernard , Torrentera Fabiola Aguilar , De Baetselier Patrick , Leo Oberdan , Carlier Yves 
Published: April 2003

ABSTRACTCells of the dendritic cell (DC) lineage, by their unique ability to stimulate naive T cells, may be of crucial importance in the development of protective immune responses toLeishmaniaparasites. The aim of this study was to compare the impact ofL. majorinfection on DCs in BALB/c (susceptible, developing Th2 responses), C57BL/6 (resistant, developing Th1 responses), and tumor necrosis factor (TNF)−/−C57BL/6 mice (susceptible, developing delayed and reduced Th1 responses). We analyzed by immunohistochemistry the phenotype of infected cells in vivo. Granulocytes (GR1+) and macrophages (CD11b+) appear as the mainly infected cells in primary lesions. In contrast, cells expressing CD11c, a DC specific marker, are the most frequently infected cells in draining lymph nodes of all mice tested. These infected CD11c+cells harbored a particular morphology and cell surface phenotype in infected C57BL/6 and BALB/c mice. CD11c+infected cells from C57BL/6 and TNF−/−C57BL/6 mice displayed a weak parasitic load and a dendritic morphology and frequently expressed CD11b or F4/80 myeloid differentiation markers. In contrast, some CD11c+infected cells from BALB/c mice were multinucleated giant cells. Giant cells presented a dramatic accumulation of parasites and differentiation markers were not detectable at their surface. In all mice, lymph node CD11c+infected cells expressed a low major histocompatibility complex II level and no detectable CD86 expression. Our results suggest that infected CD11c+DC-like cells might constitute a reservoir of parasites in lymph nodes.
Strain-Specific Association of Cytotoxic Activity and Virulence of ClinicalStaphylococcus aureusIsolates
Authors: Krut Oleg , Utermöhlen Olaf , Schlossherr Xenia , Krönke Martin 
Published: April 2003

ABSTRACTStaphylococcus aureushas been shown to invade and induce the death of various cell types. Here we investigate whether the cytotoxicity of intracellularS. aureusis a general feature or rather characteristic of individualS. aureusstrains. The majority of 23 randomly collected clinicalS. aureusisolates were killed inside keratinocytes and fibroblasts, indicating that the uptake ofS. aureusrepresents an important mechanism of cell-autonomous host defense. However, seven independentS. aureusisolates survived intracellularly and induced significant cytotoxicity for their host cells. Subcloning analysis revealed that the ability or inability to kill host cells is a stable, apparently genetically determined trait of a givenS. aureusisolate. We show that noncytotoxic strains but not cytotoxic strains colocalize with the lysosomal marker LAMP-1, suggesting that only cytotoxic strains escape degradation by the endolysosomal pathway. In a mouse septicemic model, cytotoxicS. aureusisolates produce significantly greater lethality (96%) compared to noncytotoxic strains (41%), which corresponds to 23-, 63-, and 30,000-fold increases of bacterial loads in the liver, spleen, and kidney, respectively. Finally, cytotoxicS. aureusstrains produce clinically apparent arthritis in mice at a greater frequency than compared to noncytotoxicS. aureusstrains. The results of our study unravel a previously unrecognized dichotomy of cytotoxic and noncytotoxicS. aureusisolates, which may play an important role in the dissemination of, and mortality induced by,S. aureusinfection.