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At least 289 records · Page 16Linked to original sources
PubMed1994

Cytokine-mediated regulation of chronic intestinal helminth infection.

Most inbred strains of mouse infected with the intestinal nematode Trichuris muris are resistant to infection expelling the parasite before adult worms establish. However, a few susceptible strains exist that are incapable of worm expulsion and harbor chronic infections of mature adult worms. Analyses of in vitro cytokine production by cells from the draining lymph node (mesenteric lymph node) have indicated that expulsion phenotype is tightly correlated with the selective expansion of helper T cells (Th) of the Th1 or Th2 cell subset within the mesenteric lymph node, resulting in susceptibility and resistance to T. muris, respectively. We have now confirmed and extended our in vitro observations in a series of experiments involving the in vivo manipulation of host cytokine levels. Depletion of interferon (IFN)-gamma in normally susceptible mice resulted in expulsion of the parasite, representing the first evidence for a role for IFN-gamma in the establishment of chronic helminth infection. Blocking interleukin (IL)-4 function in normally resistant animals prevented the generation of a protective immune response allowing adult stages of the parasite to develop. Conversely the administration of IL-4 to a normally susceptible host facilitated expulsion and indeed enabled established adult worms to be expelled when administered late in infection. In all cases assessment of a variety of in vivo parameters indicative of a Th1- or Th2-type response (parasite-specific immunoglobulin (Ig) G2a and the parasite-specific IgG1, total IgE levels and intestinal mastocytosis, respectively) demonstrated that the in vivo modulation of a Th1- or Th2-specific cytokine allowed the reciprocal Th cell subset to expand and become dominant with dramatic consequences for worm expulsion.

Animals↗
PubMed1996

Genetic conflicts.

Self-promoting elements (also called ultraselfish genes, selfish genes, or selfish genetic elements) are vertically transmitted genetic entities that manipulate their "host" so as to promote their own spread, usually at a cost to other genes within the genome. Examples of such elements include meiotic drive genes and cytoplasmic sex ratio distorters. The spread of a self-promoting element creates the context for the spread of a suppressor acting within the same genome. We may thus say that a genetic conflict exists between different components of the same genome. Here we investigate the properties of such conflicts. First we consider the potential diversity of genomic conflicts and show that every genetic system has potential conflicts. This is followed by analysis of the logic of conflicts. Just as Evolutionarily Stable Strategy (ESS) terminology provides a short cut for discussion of much in behavioral ecology, so the language of modifier analysis provides a useful terminology on which to base discussions of conflicts. After defining genetic conflict, we provide a general analysis of the conflicting parties, and note a distinction between competing and conflicting genes. We then provide a taxonomy of possible short- and long-term outcomes of conflicts, noting that potential conflict in an unconstrained system can never be removed, and that the course of evolution owing to conflict is often unpredictable. The latter is most particularly true for strong conflicts in which suppressors may take surprising forms. The possibility of extended conflicts in the form of "arms races" between element and suppressor is illustrated. The peculiar redundancy of these systems is one possible trace of conflict, and others are discussed. That homologous conflicts may find highly different expression is discussed by referring to the mechanistic differences that are thought to underlie the action of the two best-described meiotic drive genes, and by the multiplicity of forms of cytoplasmic sex ratio distorters. The theoretical analysis establishes a logical basis for thinking about conflicts, but fails to establish the importance of conflict in evolution. We illustrate this contentious issue through consideration of some phenomena for whose evolution conflict has been proposed as an important force: the evolution of sex, sex determination, species, recombination, and uniparental inheritance of cytoplasmic genes. In general, it is proposed that conflict may be a central force in the evolution of genetic systems. We conclude that an analysis of conflict and its general importance in evolution is greatly aided by application of the concept of genetic power. We consider the possible components of genetic power and ask whether and how power evolves.

Animals↗
PubMed1992

Gram-negative sepsis and the adult respiratory distress syndrome.

Gram-negative sepsis has dramatically increased in frequency throughout the twentieth century in the United States. Currently, approximately 200,000 patients develop gram-negative sepsis each year in this country. Of these, about one-quarter develop the adult respiratory distress syndrome (ARDS). Among these critically ill patients, mortality is estimated at 60%-90%. In the complex series of events leading to acute lung injury in gram-negative sepsis, endotoxin is the proximal mediator. Although endotoxin may be capable of causing direct injury to the pulmonary endothelium, its primary role is as a trigger activating inflammatory agents, including complement, neutrophils, and platelets, and inducing the production of cytokines and arachidonic acid metabolites. The end results are impairment of the endothelial barrier, diffusely increased capillary permeability, and adherence of neutrophils to the endothelium with subsequent migration into the tissues. The consequent clinical syndrome is one of acute respiratory distress with pulmonary edema, poorly compliant lungs, and refractory hypoxemia. Endothelial injury often becomes widespread, leading to the failure of multiple organs, including the kidneys, brain, intestine, and liver. Conventional therapy consists of supplemental oxygen, positive end-expiratory pressure, inotropic agents, fluid management, and antibiotics aimed at the offending pathogen. Recent discoveries regarding the mediators of sepsis as well as the expansion of the biotechnological armamentarium have provided clinicians with a plethora of new tools with which to manipulate the host's inflammatory response. The challenge for the next decade will be to ensure the safety, efficacy, and cost-effective use of these expensive but potentially lifesaving immunomodulators, singly or in combination, as adjuvant therapy.

Endotoxins↗
PubMed1996

Risk factors for fungemia in children infected with human immunodeficiency virus: a case-control study.

To define the risk factors related to the occurrence of fungemia in children infected with human immunodeficiency virus (HIV), we performed a matched case-control study. During a 6-year period (1987-1993), fungemia developed in 22 (6.3%) of 347 HIV-infected children observed at the Pediatric Branch of the National Cancer Institute. Each of these 22 cases was matched by age and gender with three controls. Multiple logistic regression indicated that the best predictor of fungemia in this population was the presence of a central venous catheter placed for > 90 days (P < .00001), followed by a group of risk factors composed of 10 independent variables adjusted for a CD4 cell count of < 100/MicroL (P < .045). Those variables included treatment with more than three antibiotics, treatment with more than three parenteral antibiotics, > 30 days of antibiotic treatment, bacterial infections, > 30 days in the hospital, hypoalbuminemia, C3 (Centers for Disease Control and Prevention) classification of HIV infection, and malnourishment. We conclude that prolonged placement of central venous catheters is the most important risk factors for fungemia in HIV-infected children and that the risk of fungemia is further influenced by antibacterial therapy, catheter manipulation, and host response.

Adolescent↗
PubMed2004

The lung in sepsis: fueling the fire.

Advances in our understanding of the molecular mechanisms underlying the pathophysiology of sepsis have generated considerable efforts in manipulating the host response during this frequently lethal condition. While existing trials of immune modulation have been largely unsuccessful, an appreciation for the roles of individual organ systems in sepsis is important to enable clinicians to discern how each functions as both a target for injury and a contributor to the derangement in homeostasis seen in sepsis. Such awareness will encourage treatment decisions aimed at optimizing conventional therapy while minimizing the adverse effects of supportive care, and it may also guide the incorporation of newer immunomodulatory therapeutics into our existing modalities. This article discusses the lung's response to sepsis, from the standpoint of organ dysfunction related to sepsis as well as its participation in the generation and maintenance of the systemic inflammatory state.

Animals↗
PubMed1997

Donor-dependent and dose-dependent variation in the induction of T lymphocyte locomotion in a three-dimensional collagen matrix system by a mistletoe preparation (Iscador).

Controlled activation of non-specific and specific immune defence mechanisms can beneficially manipulate the host's ability to attack malignant cells. In this context, migration and tissue distribution of immunocompetent cells may be prerequisites for an efficient immune surveillance. The effect of various non-cytotoxic concentrations of the Viscum album L. (mistletoe) preparation Iscadore QuFrF on the locomotory activity of immunomagnetically isolated human CD4+ and CD8+ T lymphocytes from healthy donors was investigated. Cellular migration was examined within a three-dimensional collagen matrix. Donor-dependent variations in baseline activities of spontaneously locomoting T cells were accompanied by individual response patterns of T cells from different donors in the presence of various concentrations of mistletoe preparation (0.25-2.5 micrograms/ml). Using the three-dimensional collagen matrix assay an induction of locomotory activity was detected in a highly reproducible fashion although the optimal concentration of mistletoe preparation and the time point of maximal response were individual for each donor. Our data suggest that the direct stimulation of T-cell migration by mistletoe components may modulate the system of immune surveillance and recognition in patients under mistletoe therapy.

Antineoplastic Agents, Phytogenic↗
PubMed2003

Taurine attenuates calcium-dependent, Fas-mediated neutrophil apoptosis.

The pathway involved in Fas-mediated neutrophil apoptosis remains to be fully elucidated. We examined whether this pathway involved either oxygen-dependent or calcium-dependent mechanisms. We also investigated whether taurine, a powerful antioxidant and regulator of intracellular calcium fluxes, could inhibit Fas-mediated neutrophil apoptosis. Neutrophils were stimulated with Fas monoclonal antibody in the presence or absence of taurine. Fas receptor ligation resulted in significant neutrophil apoptosis at 18 h. Engagement of the Fas receptor rapidly resulted in a significant decrease in intracellular calcium. Apoptosis was inhibited and intracellular calcium levels were maintained in the presence of calcium ionophore A23187 or taurine. Fas ligation did not result in an increase in intracellular reactive oxygen species. We have demonstrated that Fas-mediated neutrophil apoptosis occurs after a decrease in intracellular calcium and is reactive oxygen intermediate independent. Furthermore, the amino acid taurine attenuates this pathway of neutrophil apoptosis by calcium regulation. This newly identified role of taurine in the inhibition of Fas-mediated neutrophil apoptosis may have significant implications for future manipulation of host pro-inflammatory cell function.

Apoptosis↗
PubMed2004

Characterization of a 'Bacteroidetes' symbiont in Encarsia wasps (Hymenoptera: Aphelinidae): proposal of 'Candidatus Cardinium hertigii'.

Previously, analysis of 16S rDNA sequences placed a newly discovered lineage of bacterial symbionts of arthropods in the 'Bacteroidetes'. This symbiont lineage is associated with a number of diverse host reproductive manipulations, including induction of parthenogenesis in several Encarsia parasitoid wasps (Hymenoptera: Aphelinidae). In this study, electron microscopy and phylogenetic analysis of the 16S rRNA and gyrB genes of symbionts from Encarsia hispida and Encarsia pergandiella are used to describe and further characterize these bacteria. Phylogenetic analyses based on these two genes showed that the Encarsia symbionts are allied with the Cytophaga aurantiaca lineage within the 'Bacteroidetes', with their closest described relative being the acanthamoeba symbiont 'Candidatus Amoebophilus asiaticus'. The Encarsia symbionts share 97 % 16S rDNA sequence similarity with Brevipalpus mite and Ixodes tick symbionts and 88 % sequence similarity with 'Candidatus A. asiaticus'. Electron microscopy revealed that many of the bacteria found in the ovaries of the two Encarsia species contained a regular, brush-like array of microfilament-like structures that appear to be characteristic of the symbiont. Finally, the role of this bacterium in parthenogenesis induction in E. hispida was confirmed. Based on phylogenetic analyses and electron microscopy, classification of the symbionts from Encarsia as 'Candidatus Cardinium hertigii' is proposed.

Animals↗
PubMed2004

A new member of the interleukin 10-related cytokine family encoded by a poxvirus.

Poxviruses express numerous proteins involved in manipulating the host immune response. Analysis of the primary sequence and predicted structure of the 134R protein of Yaba-like disease virus (Y134R) indicated that it is similar to cellular proteins of the IL-10 family, specifically IL-19, IL-20 and IL-24. A flag-tagged Y134R was expressed from mammalian cells and identified as a secreted, monomeric glycoprotein that stimulated signal transduction from class II cytokine receptors IL-20Ralpha/IL-20Rbeta (IL-20R type1) and IL-22R/IL-20Rbeta (IL-20R type 2). Y134R induced phosphorylation of signal transducers and activators of transcription, their translocation to the nucleus and the induction of reporter gene expression. In contrast, Y134R was unable to induce similar responses from either the IL-22 or IFN-lambda (IL-28A, IL-28B, IL-29) class II cytokine receptors. To examine the role Y134R plays during a poxvirus infection, a vaccinia virus recombinant expressing Y134R was constructed and tested in a murine intranasal infection model. Compared with control viruses, the virus expressing Y134R had a reduced virulence, manifested by reduced weight loss, signs of illness and virus titres in infected organs. These results demonstrate that Y134R is a new viral member of the IL-10-related cytokine family and that its activity in vivo affects virus virulence.

Amino Acid Sequence↗
PubMed2005

Identification of candidate sialome components expressed in ixodid tick salivary glands using secretion signal complementation in mammalian cells.

Ixodid ticks manipulate mammalian host pathways by secreting molecules from salivary glands. Novel cDNAs containing functional secretion signals were isolated from ixodid tick salivary glands using a signal sequence trap. Only 15/61 Rhipicephalus appendiculatus and 1/7 Amblyomma variegatum cDNAs had significant identity (< 1e-15) to previously identified sequences. Polypeptides that may interact with host pathways included a kinase inhibitor. Two proteins encoded homologues of the yolk protein vitellogenin and seventeen contained glycine-rich motifs. Four proteins without sequence matches had conserved structural folds, identified using a Threading algorithm. Predicted secretion signals were between fifteen and fifty-seven amino acids long. Four homologous polymorphic proteins contained conserved (26/27 residues) signal peptides. Ten functional tick secretion signals could not be unambiguously identified using predictive algorithms.

Amino Acid Motifs↗
PubMed1996

Genetic control of immunity to Heligmosomoides polygyrus: presentation of promiscuous antigens to parasite-specific T cell hybridomas.

The role of MHC class II in the presentation of Heligmosomoides polygyrus antigens has been investigated, using a number of T cell hybridomas produced in A and E positive and negative mice. By using fixed and irradiated antigen presenting cells (APC), further evidence has emerged, to support earlier data, that there can be differential processing requirements during the presentation of H. polygyrus antigens by A and E molecules. In concordance with these earlier observations, this work provides further evidence than individual T cells can respond to antigen when presented by more than one MHC molecule. Previously, this evidence has been restricted to individual MHC molecules of the same haplotype, but these data show that H. polygyrus produces antigens which can be presented by both syngeneic and allogeneic MHC molecules. These antigens do not appear to be synonymous with the previously described H. polygyrus superantigen, as presentation is restricted to specific MHC haplotypes. It is proposed that H. polygyrus may produce these antigenic molecules as part of its strategy to manipulate the host immune system.

Animals↗
PubMed2004

The role and regulation of programmed cell death in plant-pathogen interactions.

It is commonly known that animal pathogens often target and suppress programmed cell death (pcd) pathway components to manipulate their hosts. In contrast, plant pathogens often trigger pcd. In cases in which plant pcd accompanies disease resistance, an event called the hypersensitive response, the plant surveillance system has learned to detect pathogen-secreted molecules in order to mount a defence response. In plants without genetic disease resistance, these secreted molecules serve as virulence factors that act through largely unknown mechanisms. Recent studies suggest that plant bacterial pathogens also secrete antiapoptotic proteins to promote their virulence. In contrast, a number of fungal pathogens secrete pcd-promoting molecules that are critical virulence factors. Here, we review recent progress in determining the role and regulation of plant pcd responses that accompany both resistance and susceptible interactions. We also review progress in discerning the mechanisms by which plant pcd occurs during these different interactions.

Apoptosis↗
PubMed2006

Ringing the alarm bells: signalling and apoptosis in influenza virus infected cells.

Small RNA viruses such as influenza viruses extensively manipulate host-cell functions to support their replication. At the same time the infected cell induces an array of defence mechanisms to fight the invader. These processes are mediated by a variety of intracellular signalling cascades. Here we will review the current knowledge of functional kinase signalling and apoptotic events in influenza virus infected cells and how these viruses have learned to misuse these cellular responses for efficient replication.

Animals↗
PubMed1999

Type III secretion machines and the pathogenesis of enteric infections caused by Yersinia and Salmonella spp.

Salmonella and Yersinia spp. infect the intestinal tract of humans. Although these organisms cause fundamentally different diseases, each pathogen relies on type III secretion machines to either inject virulence factors into the cytosol of eukaryotic cells or release toxins into the extracellular milieu. Type III secretion machines are composed of many different subunits and export several polypeptides with unique substrate requirements. During Salmonella pathogenesis, the type III machine encoded by the Salmonella pathogenicity island (SPI)-1 genetic element functions to cause invasion of the intestinal epithelium, whereas another type III machine (SPI-2) is required for survival in macrophages. Yersinia enterocolitica and Yersinia pseudotuberculosis employ type III machines to resist macrophage phagocytosis and to manipulate the host's immune response, thereby colonizing intestinal lymphoid tissues. We describe what is known about the pathogenic functions of virulence factors secreted by type III machines. Furthermore, type III secretion machines may be exploited for the injection of recombinant proteins, a strategy that has already been successfully employed to elicit a cell-mediated immune response.

Animals↗
PubMed1998

Chronic active hepatitis induced by Helicobacter hepaticus in the A/JCr mouse is associated with a Th1 cell-mediated immune response.

Helicobacter hepaticus infection in A/JCr mice results in chronic active hepatitis characterized by perivascular, periportal, and parenchymal infiltrates of mononuclear and polymorphonuclear cells. This study examined the development of hepatitis and the immune response of A/JCr mice to H. hepaticus infection. The humoral and cell-mediated T helper immune response was profiled by measuring the postinfection (p.i.) antibody response in serum, feces, and bile and by the production of cytokines and proliferative responses by splenic mononuclear cells to H. hepaticus antigens. Secretory immunoglobulin A (IgA) and systemic IgG2a antibody developed by 4 weeks p.i. and persisted through 12 months. Splenocytes from infected mice proliferated and produced more gamma interferon (IFN-gamma) than interleukin-4 (IL-4) or IL-5 when cultured with H. hepaticus outer membrane proteins. The predominantly IgG2a antibody response in serum and the in vitro production of IFN-gamma in excess of IL-4 or IL-5 are consistent with a Th1 immune response reported in humans and mice infected with Helicobacter pylori and Helicobacter felis, respectively. Mice infected with H. hepaticus developed progressively severe perivascular, periportal, and hepatic parenchymal lesions consisting of lymphohistiocytic and plasmacytic cellular infiltrates. In addition, transmural typhlitis was observed at 12 months p.i. The characterization of a cell-mediated Th1 immune response to H. hepaticus infection in the A/JCr mouse should prove valuable as a model for experimental regimens which manipulate the host response to Helicobacter.

Animals↗
PubMed2002

Uptake of Aspergillus fumigatus Conidia by phagocytic and nonphagocytic cells in vitro: quantitation using strains expressing green fluorescent protein.

Several pathogenic fungal organisms enter eukaryotic cells and manipulate the host cell environment to favor their own growth and survival. Aspergillus fumigatus is a saprophytic fungus that causes invasive lung disease in the immunocompromised host. To determine whether A. fumigatus could enter eukaryotic cells, we studied the uptake of two different GFP-expressing A. fumigatus strains into A549 lung epithelial cells, human umbilical vein endothelial (HUVE) cells, and J774 murine macrophages in vitro. A549 cells internalized 30% of the bound conidia whereas HUVE and J774 cells internalized 50 and 90%, respectively. Conidia within A549 cells remained viable for 6 h; however, 60 to 80% of conidia within J774 cells were killed after only 4 h. Live and heat-killed conidia were internalized to the same extent by A549 cells. After 6 h, almost none of the conidia inside A549 cells had germinated, whereas extracellular conidia had developed germ tubes. Internalization of conidia by A549 cells was a temperature-dependent process and required rearrangement of the underlying host cell cytoskeleton; uptake was inhibited by 75% with 0.5 microM cytochalasin D and by 65% with 5 microM colchicine. Fluorescent labeling of infected A549 cells with rhodamine phalloidin provided visible evidence of cytoskeletal alteration as many of the intracellular conidia were contained in actin-coated phagosomes. These data provide evidence that significant numbers of A. fumigatus conidia can be internalized by nonprofessional phagocytes in vitro and these cells may serve as reservoirs for immune cell evasion and dissemination throughout the host.

Actin Cytoskeleton↗
PubMed2006

Modulation of Kaposi's sarcoma-associated herpesvirus infection and replication by MEK/ERK, JNK, and p38 multiple mitogen-activated protein kinase pathways during primary infection.

Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with Kaposi's sarcoma, a dominant AIDS-related tumor of endothelial cells, and several other lymphoproliferative malignancies. While activation of the phosphatidylinositol 3-kinase-protein kinase C-MEK-ERK pathway is essential for KSHV infection, we have recently shown that KSHV also activates JNK and p38 mitogen-activated protein kinase (MAPK) pathways during primary infection (J. Xie, H. Y. Pan, S. Yoo, and S.-J. Gao, J. Virol. 79:15027-15037, 2005). Here, we found that activation of both JNK and p38 pathways was also essential for KSHV infection. Inhibitors of all three MAPK pathways reduced KSHV infectivity in both human umbilical vein endothelial cells (HUVEC) and 293 cells. These inhibitory effects were dose dependent and occurred at the virus entry stage of infection. Consistently, inhibition of all three MAPK pathways with dominant-negative constructs reduced KSHV infectivity whereas activation of the ERK pathway but not the JNK and p38 pathways enhanced KSHV infectivity. Importantly, inhibition of all three MAPK pathways also reduced the yield of infectious virions during KSHV productive infection of HUVEC. While the reduction of infectious virions was in part due to the reduced infectivity, it was also the result of direct modulation of KSHV lytic replication by the MAPK pathways. Accordingly, KSHV upregulated the expression of RTA (Orf50), a master transactivator of KSHV lytic replication, and activated its promoter during primary infection. Furthermore, KSHV activation of RTA promoter during primary infection was modulated by all three MAPK pathways, predominantly through their downstream target AP-1. Together, these results indicate that, by modulating multiple MAPK pathways, KSHV manipulates the host cells to facilitate its entry into the cells and postentry productive lytic replication during primary infection.

Cells, Cultured↗