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PubMed2004

Transcriptional regulator CTCF controls human interleukin 1 receptor-associated kinase 2 promoter.

Immune responses to invading pathogens are mediated largely through a family of transmembrane Toll-like receptors and modulated by a number of downstream effectors. In particular, a family of four interleukin 1 receptor-associated kinases (IRAK) regulates responsiveness to bacterial endotoxins. Pharmacological targeting of particular IRAK components may be beneficial for treatment of bacterial infections. Here, we studied transcriptional regulation of the human IRAK2 gene. Analysis of the IRAK2 promoter region reveals putative binding sites for several transcriptional factors, including ZIP (EGR1 and SP1), CTCF and AP-2beta. Deletion of the ZIP or AP-2 sites did not significantly affect IRAK2 promoter activity in naive and endotoxin-treated mononuclear cells, in dormant and activated Jurkat T-cells, in lung and kidney cells. In contrast, we found that CTCF plays a major role in IRAK2 transcription. An electrophoretic mobility shift assay of the DNA fragments containing the IRAK2 CpG island, revealed a single high-affinity binding site for the transcriptional regulator and a chromatin insulator protein, CTCF. This assay revealed a CTCF-binding site within the mouse Irak2 promoter. The presence of the CTCF protein in human IRAK2 promoter was confirmed by chromatin immunoprecipitation assay. Specific residues that interacted with the CTCF protein, were identified by methylation interference assay. In all cell lines analyzed, including cells of lung, renal, monocytic and T-cell origin, the IRAK2 luciferase reporter construct, containing an intact CTCF-binding site, showed strong promoter activity. However, IRAK2 promoter activity was decreased dramatically for the constructs with a mutated CTCF-binding site.

Animals↗

PubMed2005

Interaction of Helicobacter pylori with host cells: function of secreted and translocated molecules.

Secreted proteins are of general interest from the perspective of bacteria-host interaction. The gastric bacterial pathogen Helicobacter pylori uses a set of secreted and translocated proteins--including outer membrane adhesins, secreted extracellular enzymes and translocated effector proteins--to adapt to its extraordinary habitat, the gastric mucosa. Two major virulence factors of H. pylori are the vacuolating cytotoxin (VacA) and the cag type-IV secretion system and its translocated effector protein, cytotoxin-associated antigen A (CagA). VacA targets not only epithelial cells, but also cells of the immune system and induces immunosuppression. CagA has been shown to interact with a growing set of eucaryotic signaling molecules in phosphorylation-dependent and -independent ways.

Animals↗

PubMed2005

Bacterial toxins that modulate host cell-cycle progression.

The mammalian cell cycle is involved in many processes--such as immune responses, maintenance of epithelial barrier functions, and cellular differentiation--that affect the growth and colonization of pathogenic bacteria. Therefore it is not surprising that many bacterial pathogens manipulate the host cell cycle with respect to these functions. Cyclomodulins are a growing family of bacterial toxins and effectors that interfere with the eukaryotic cell cycle. Here, we review some of these cyclomodulins such as cytolethal distending toxins, vacuolating cytotoxin, the polyketide-derived macrolide mycolactone, cycle-inhibiting factor, cytotoxic necrotizing factors, dermonecrotic toxin, Pasteurella multocida toxin and cytotoxin-associated antigen A. We describe and compare their effects on the mammalian cell cycle and their putative role in disease, commensalism and symbiosis. We also discuss a possible link between these cyclomodulins and cancer.

Animals↗

PubMed2006

Who comes first? How plant pathogenic bacteria orchestrate type III secretion.

The type III secretion system (T3SS) is a key pathogenicity factor of many Gram-negative plant and animal pathogens and is also present in some symbiotic bacteria. T3SSs are highly conserved, complex molecular injection machines that translocate bacterial effector proteins directly into eukaryotic cells. Recent genetic, biochemical and structural studies revealed that the activity of the T3SS is regulated by common mechanisms in different bacterial species. In many cases, type III secretion is activated upon host cell contact and depends on specific control proteins, including transcriptional regulators and type III secretion chaperones.

Bacterial Proteins↗

PubMed2003

The control of apoptosis in lymphocyte selection.

The stochastic nature of rearrangement and diversification of the gene segments encoding immunoglobulins (Igs) and T cell receptors (TCRs) inevitably gives rise to immature B and T lymphocytes that lack antigen receptors or express useless or dangerous (self-antigen-specific) ones. Signaling through antigen receptors promotes survival, proliferative expansion and further differentiation of useful cells and deletion of the useless and dangerous ones. During immune responses, pathogen-specific B and T lymphocytes, as well as cells of the innate immune system, undergo extensive proliferation and develop effector functions, such as antibody secretion, cytotoxicity or cytokine production. To prevent tissue damage by these effector molecules, activated lymphocytes are removed when an infection has been overcome. Together with other mechanisms, including developmental arrest and induction of unresponsiveness (anergy), programmed cell death (apoptosis) of autoreactive lymphocytes safeguards immunological tolerance to self and assists in the development of an effective immune system. We have been investigating the molecular mechanisms that control programmed cell death. This review describes some of our experiments using transgenic and knockout mice, which overexpress or lack apoptosis regulators, that led to discoveries on how life and death decisions are made during development and functioning of the immune system.

Animals↗

PubMed1997

Dependence of the adaptive immune response on innate immunity: some questions answered but new paradoxes emerge.

Recently a new model of vertebrate immunity has been gaining popularity. In this new model it is hypothesized that activation of innate immunity is a prerequisite for an adaptive immune response to an antigen. Following activation the innate system induces key costimulator molecules on APC, which are essential for antigen-driven clonal expansion of T and B cells. The model largely explains the need for adjuvants in the induction of adaptive immunity, provides a possible mechanism for the immune system to perceive the biological nature of a pathogen and thereby produce the most effective immune response, and transfers much of the onus of self-non-self discrimination from the adaptive to the innate immune system. In the present article we highlight two paradoxes raised by the new model. First, by linking adaptive immunity to innate recognition the immune system is unable to take full advantage of the genetic diversity of T and B cell antigen receptors. Thus, the ability of the immune system to combat a pathogen is totally dependent on the efficiency of recognition by the innate system and, therefore, the germ-line mutation rate of the genes involved in the innate response. Second, if signals from the innate system induce costimulatory molecules on APC, then one would expect the accidental clonal expansion of many autoreactive T and B cells. We suggest that one means of resolving the first paradox is to propose that the major reason for the evolution of adaptive immunity was to provide, via immunological memory, resistance to reinfection, rather than simply to combat the primary infection by the pathogen. In the case of autoreactivity we suggest that autodestruction is prevented by immune responses being tightly regulated at the effector T cell level. Finally, we argue that the two paradoxes, rather than undermining the new model of immunity, highlight our lack of understanding of key elements of the vertebrate immune system.

Adaptation, Physiological↗

PubMed2000

Absence of CD40-CD40 ligand interactions in X-linked hyper-IgM syndrome does not affect differentiation of T helper cell subsets.

The aim of this study was to investigate the effect of absent CD40-CD40 ligand interactions in patients with X-linked hyper-IgM syndrome (XHIGM) on the generation of Th1 and Th2 immunity. Whole blood from patients and sex- and age-matched controls was stimulated with phorbol myristate acetate (PMA) and calcium ionophore A23187 in the presence of Brefeldin A. After 5 h, cellular production of interferon-gamma, IL-4, tumour necrosis factor-alpha and IL-2 was measured by intracellular cytokine staining and flow cytometry. This method has been shown previously to preferentially activate memory T cells and in preliminary experiments cells making these cytokines were found to be predominantly CD45RO+. No differences in the proportion of T cells (CD3+) or T cell subsets (CD4+/CD8+) secreting these cytokines between XHIGM patients and age- and sex-matched controls were observed. In addition, production of IL-12 and IL-6 by monocytes in response to lipopolysaccharide and CD40 stimulation was equivalent in patients and controls. These results suggest that development of Th1 or Th2 memory cells in patients with XHIGM is unaffected by the absence of functional CD40 ligand. Rather, the susceptibility of these patients to intracellular pathogens, such as Pneumocystis carinii and Cryptosporidium parvum, is more likely to be due to an inability to activate the effector arm of the cellular immune response.

Adolescent↗

PubMed2001

Identification of functional regions within invasion plasmid antigen C (IpaC) of Shigella flexneri.

Shigella flexneri causes bacillary dysentery with symptoms resulting from the inflammation that accompanies bacterial entry into the cells of the colonic epithelium. The effectors of S. flexneri invasion are the Ipa proteins, particularly IpaB and IpaC, which are secreted at the host-pathogen interface following bacterial contact with a host cell. Of the purified Ipa proteins, only IpaC has been shown to possess quantifiable in vitro activities that are related to cellular invasion. In this study, ipaC deletion mutants were generated to identify functional regions within the IpaC protein. From these data, we now know that the N-terminus and an immunogenic central region are not required for IpaC-dependent enhancement of cellular invasion by S. flexneri. However, to restore invasiveness to an ipaC null mutant of S. flexneri, the N-terminus is essential, because IpaC mutants lacking the N-terminus are not secreted by the bacterium. Deletion of the central hydrophobic region eliminates IpaC's ability to interact with phospholipid membranes, and fusion of this region to a modified form of green fluorescent protein converts it into an efficient membrane-associating protein. Meanwhile, deletion of the C-terminus eliminates the mutant protein's ability to establish protein-protein contacts with full-length IpaC. Interestingly, the mutant form of ipaC that restores partial invasiveness to the S. flexneri ipaC null mutant also restores full contact-mediated haemolysis activity to this bacterium. These data support a model in which IpaC possesses a distinct functional organization that is important for bacterial invasion. This information will be important in defining the precise role of IpaC in S. flexneri pathogenesis and in exploring the potential effects of purified IpaC at mucosal surfaces.

Antigens, Bacterial↗

PubMed2002

To be or Not to be ridded?--That is the question addressed by the associative antigen recognition model.

The reasons that germline-encoded recognitive sites cannot sort the immune system's large and random somatically generated repertoire into anti-Not-to-be-ridded ('self ') and anti-To-be-ridded ('nonself ') specificities are analysed. The immune system cannot use 'nonself '-markers of To-be-ridded antigens ('Danger', toll receptors, pathogenicity, localization, etc.) to sort the repertoire; it may, however, use them to determine the magnitude and class of the effector response.

Animals↗

PubMed2003

A Pseudomonas syringae type III effector suppresses cell wall-based extracellular defense in susceptible Arabidopsis plants.

Bacterial effector proteins secreted through the type III secretion system (TTSS) play a crucial role in causing plant and human diseases. Although the ability of type III effectors to trigger defense responses in resistant plants is well understood, the disease-promoting functions of type III effectors in susceptible plants are largely enigmatic. Previous microscopic studies suggest that in susceptible plants the TTSS of plant-pathogenic bacteria transports suppressors of a cell wall-based plant defense activated by the TTSS-defective hrp mutant bacteria. However, the identity of such suppressors has remained elusive. We discovered that the Pseudomonas syringae TTSS down-regulated the expression of a set of Arabidopsis genes encoding putatively secreted cell wall and defense proteins in a salicylic acid-independent manner. Transgenic expression of AvrPto repressed a similar set of host genes, compromised defense-related callose deposition in the host cell wall, and permitted substantial multiplication of an hrp mutant. AvrPto is therefore one of the long postulated suppressors of an salicylic acid-independent, cell wall-based defense that is aimed at hrp mutant bacteria.

Arabidopsis↗

PubMed2005

Role of predicted transmembrane domains for type III translocation, pore formation, and signaling by the Yersinia pseudotuberculosis YopB protein.

YopB is a 401-amino-acid protein that is secreted by a plasmid-encoded type III secretion system in pathogenic Yersinia species. YopB is required for Yersinia spp. to translocate across the host plasma membrane a set of secreted effector proteins that function to counteract immune signaling responses and to induce apoptosis. YopB contains two predicted transmembrane helices (residues 166 to 188 and 228 to 250) that are thought to insert into the host plasma membrane during translocation. YopB is also required for pore formation and host-cell-signaling responses to the type III machinery, and these functions of YopB may also require membrane insertion. To elucidate the importance of membrane insertion for YopB function, YopB proteins containing helix-disrupting double consecutive proline substitutions in the center of each transmembrane domain were constructed. Yersinia pseudotuberculosis strains expressing the mutant YopB proteins were used to infect macrophages or epithelial cells. Effector translocation, pore formation, and host-cell-signaling responses were studied. Introduction of helix-disrupting substitutions into the second transmembrane domain of YopB resulted in a nonfunctional protein that was not secreted by the type III machinery. Introduction of helix-disrupting substitutions into the first transmembrane domain of YopB resulted in a protein that was fully functional for secretion and for interaction with YopD, another component of the translocation machinery. However, the YopB protein with helix-disrupting substitutions in the first transmembrane domain was partially defective for translocation, pore formation, and signaling, suggesting that all three functions of YopB involve insertion into host membrane.

Animals↗

PubMed2004

Microarray-based analysis of the Staphylococcus aureus sigmaB regulon.

Microarray-based analysis of the transcriptional profiles of the genetically distinct Staphylococcus aureus strains COL, GP268, and Newman indicate that a total of 251 open reading frames (ORFs) are influenced by sigmaB activity. While sigmaB was found to positively control 198 genes by a factor of > or =2 in at least two of the three genetic lineages analyzed, 53 ORFs were repressed in the presence of sigmaB. Gene products that were found to be influenced by sigmaB are putatively involved in all manner of cellular processes, including cell envelope biosynthesis and turnover, intermediary metabolism, and signaling pathways. Most of the genes and/or operons identified as upregulated by sigmaB were preceded by a nucleotide sequence that resembled the sigmaB consensus promoter sequence of Bacillus subtilis. A conspicuous number of virulence-associated genes were identified as regulated by sigmaB activity, with many adhesins upregulated and prominently represented in this group, while transcription of various exoproteins and toxins were repressed. The data presented here suggest that the sigmaB of S. aureus controls a large regulon and is an important modulator of virulence gene expression that is likely to act conversely to RNAIII, the effector molecule of the agr locus. We propose that this alternative transcription factor may be of importance for the invading pathogen to fine-tune its virulence factor production in response to changing host environments.

Bacterial Proteins↗

PubMed2004

Yersinia enterocolitica type III secretion: evidence for the ability to transport proteins that are folded prior to secretion.

BACKGROUND: Pathogenic Yersinia species (Y. enterocolitica, Y. pestis, Y. pseudotuberculosis) share a type three secretion system (TTSS) which allows translocation of effector proteins (called Yops) into host cells. It is believed that proteins are delivered through a hollow needle with an inner diameter of 2-3 nm. Thus transport seems to require substrates which are essentially unfolded. Recent work from different groups suggests that the Yersinia TTSS cannot accommodate substrates which are folded prior to secretion. It was suggested that folding is prevented either by co-translational secretion or by the assistance of specific Yop chaperones (called Sycs). RESULTS: In this study we have fused YopE secretion signals of various length to the mouse dihydrofolate reductase (DHFR) in order to analyse the DHFR folding state prior to secretion. We could demonstrate that secretion-deficient as well as secretion-competent YopE-DHFR fusions complexed to SycE can be efficiently purified from Yersinia cytosol by affinity chromatography using methotrexate-agarose. This implies the folding of the DHFR fusion moiety despite SycE binding and contradicts the previously presented model of folding inhibition by chaperone binding. Secretion-deficient YopE-DHFR fusions caused severe jamming of the TTSS. This observation contradicts the co-translational secretion model. CONCLUSIONS: We present evidence that the Yersinia TTSS is familiar with the processing of transport substrates which are folded prior to secretion. We therefore predict that an unfoldase is involved in type III secretion.

Bacterial Outer Membrane Proteins↗

PubMed2006

Inflammatory bowel disease: maladaptation of the vigilant genotype in a hyper-clean world?

Children born of Asian Indian parents who are raised in environmentally hygienic Western societies appear to be highly prone to two diseases, ulcerative colitis and Crohn's disease, collectively known as inflammatory bowel disease or IBD. These ethnically Indian children are similar to an inbred mouse strain, NOD/Lt. Mice of this strain remain diabetes-free when raised in standard mouse colonies, but develop an autoimmune diabetes at high rates when kept in pathogen-free environments. I propose that certain human habitats have, over eons, selected for "vigilant genotypes," wherein combinations of alleles at critical loci result in aggressive immune responses to pathogens. This genetic configuration is adaptive in the selective environment but maladaptive in more hygienic environments, resulting in dysregulated immune effectors. One manifestation of such dysregulation is organ-specific autoimmunity, such as IBD.

Animals↗

PubMedDate not supplied

The tranquilizing injection of Yersinia proteins: a pathogen's strategy to resist host defense.

Pathogenic bacteria of the genus Yersinia possess a type III secretion apparatus by which they can inject up to six effector proteins into host cells. These so-called effector Yops (Yersinia outer proteins) disrupt cellular immune defense functions such as TNF-alpha release, O2-production or phagocytosis and thereby allow Yersinia to grow extracellularly. Recent findings indicate that the effector Yops are highly active proteins that engage in crucial eukaryotic signaling mechanisms. For instance, the translocated tyrosine phosphatase YopH dephosphorylates the focal adhesion proteins paxillin and p130Cas within target cells. Furthermore, the Yersinia effector YopP is able to induce apoptosis in macrophages presumably by blocking MAP kinase and NFKB mediated signaling events. Here we discuss recent advances concerning the intracellular targets and biochemical signaling mechanisms regulated by the translocated Yersinia effectors.

Animals↗

PubMed2005

[Fractalkine and inflammatory diseases].

The migration of leukocytes into inflamed peripheral tissues and lymphoid organs involves a cascade of molecular events finely regulated by cell adhesion molecules and chemokines. Fractalkine/CX3CL1 is a membrane-bound chemokine that functions not only as a chemoattractant but also as an adhesion molecule, and is expressed on endothelial cells activated by proinflammatory cytokines. The fractalkine receptor, CX3CR1, is expressed on cytotoxic effector lymphocytes including NK cells and cytotoxic effector T cells (T(CE)), mature monocytes/macrophages, and mucosal dendritic cells, all of which play important roles in elimination of pathogens and cancer cells. Recently, accumulating evidence in both clinical studies and animal disease models has shown that fractalkine is also involved in the pathogenesis of various chronic inflammatory diseases, such as rheumatoid arthritis and atherosclerosis. This article reviews the unique functions of fractalkine and its pathophysiological roles in various clinical conditions.

Animals↗

PubMed2005

Synergism and complementarity between human CD1 AND MHC-restricted T cells, two lymphoid subsets directed against distinct antigenic worlds.

The antigenic repertoire of T cells has long been considered as exclusively composed of proteins and peptides. This view has been recently challenged by the discovery of CD1 molecules, a set of weakly polymorphic MHC class I-related receptors able to present lipid antigens to T cells. An updated picture of the biology of human CD1-restricted T cells is provided here, which highlights the unique features of these lymphoid effectors and the way they synergize with other innate and adaptive immune players to ensure protective immunity against tumors and pathogens.

Animals↗

PubMed2001

Gene expression in antigen-specific CD8+ T cells during viral infection.

Following infection with intracellular pathogens, Ag-specific CD8(+) T cells become activated and begin to proliferate. As these cells become activated, they elaborate effector functions including cytokine production and cytolysis. After the infection has been cleared, the immune system returns to homeostasis through apoptosis of the majority of the Ag-specific effector cells. The surviving memory cells can persist for extended periods and provide protection against reinfection. Little is known about the changes in gene expression as Ag-specific cells progress through these stages of development, i.e., naive to effector to memory. Using recombinant MHC class I tetramers, we isolated Ag-specific CD8(+) T cells from mice infected with lymphocytic choriomeningitis virus at various time points and performed semiquantitative RT-PCR. We examined expression of: 1) genes involved in cell cycle control, 2) effector and regulatory functions, and 3) susceptibility to apoptosis. We found that Ag-specific CD8(+) memory T cells contain high steady-state levels of Bcl-2, BAX:, IFN-gamma, and lung Kruppel-like factor (LKLF), and decreased levels of p21 and p27 mRNA. Moreover, the pattern of gene expression between naive and memory cells is distinct and suggests that these two cell types control susceptibility to apoptosis through different mechanisms.

Animals↗