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Results for “pathogen effectors”

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PubMed1999

Central nervous system-targeted expression of the complement inhibitor sCrry prevents experimental allergic encephalomyelitis.

Although generally thought of as a T cell-driven autoimmune disease, recent studies in experimental allergic encephalomyelitis (EAE), the animal model of multiple sclerosis, suggest a significant role for innate immune mechanisms. To address the possibility that the complement system plays a central role in these diseases, we developed a transgenic mouse with astrocyte-targeted production of a soluble inhibitor of complement activation, complement receptor-related protein y (sCrry). Here, we show that sCrry transgenic mice are either fully protected against EAE or develop significantly delayed clinical signs. These results indicate that complement activation may have an essential role in the pathogenesis of the disease and that complement-mediated events may occur early during the effector phase of EAE. Furthermore, this work underscores the importance of humoral immunity in amplifying a T cell-initiated pathogenic process.

Animals↗

PubMed2001

Cysteine proteinases in tumor cell growth and apoptosis.

During their evolution tumor cells acquire and mobilize various mechanisms that crucially affect their capability of proliferation, invasiveness and metastasis. Recent findings provide evidence that tumor cell associated cysteine proteinases such as some lysosomal cathepsins and apoptotic caspases are fundamentally involved in specific developmental traits of tumor cell populations. Tumor cell exterior-associated cysteine cathepsins B and L promote tumor growth, invasion and metastasis through degradation of extracellular connective matrices and through endothelial cell growth-directed activities. On the other hand, caspases -3, -7 and -6, generated in tumor cell cytoplasm via a robust activation of their zymogens, suppress tumor cell growth, invasion and metastasis through proteolytic devitalizing and remodeling of tumor cells into readily phagocytable apoptotic corpses. Tumor cell variants that are deficient in expression of effector caspase zymogens or are capable to suppress the extrinsic and intrinsic activation mechanisms of effector caspase zymogens and the activity of effector caspases have a significant survival advantage in environments of various death stimuli. Advancements in pharmacological targeting of tumor associated pathogenic lysosomal cysteine cathepsins and in apoptotic caspases-oriented conditioning of tumor cells may substantially contribute to therapeutic control of tumor diseases.

Animals↗

PubMed1987

[Endogenous counterinflammation and immunostimulation].

It is known since a century that inflammation is the cornerstone of the resistance against pathogens at the site of penetration. Recently, it has been shown that this beneficial effect can be found in a remote site. Furthermore, it is known that, at a distance from the site of inflammation, a decreased inflammatory reaction is observed: a counterinflammation. Concerning this counterinflammation it was found, at least in mice, that this antiinflammatory effect is equivalent or even superior to those of glucocorticoids. In mice, this counterinflammation effect is observed only 6 hours following the primo-inflammation, occurs in absence of T lymphocytes and is not mediated with bioproducts of the arachidonic metabolism. The increased host resistance against pathogens occurs later (3-10 days). It is observed against fungi, bacteria, parasites and even tumour cells. Among the possible effectors of such an increased resistance, a protein was purified to homogeneity (MW = 56 Kd, pI = 5, electrophoretic mobility of the alpha 1 globulins. This protein is with interferon gamma the more potent immunostimulant. Other effectors are presently under investigation: there are proteins involved in hematopoiesis and the cytostasis of tumour cells. It is therefore evident that in the course of certain inflammatory reactions, several substances may act as potent endogenous drugs: they are true phlogautacoïds.

Animals↗

PubMed1997

Mucosal immunity--a major adaptive defence mechanism.

The epithelial glycoprotein called secretory component (SC) is quantitatively the most important receptor of the immune system because it is responsible for external transport of locally produced polymeric IgA (pIgA) to generate remarkably large amounts of secretory IgA. Antibodies of this type constitute the major mediators of specific humoral immunity. Transmembrane SC belongs to the Ig supergene family and functions as a common pIg receptor, also translocating pentameric IgM externally to form secretory IgM. The B cells responsible for mucosal pIg production are initially stimulated in organized mucosa-associated lymphoepithelial structures, particularly the Peyer's patches in the distal small intestine; from these inductive site they migrate as memory cells to exocrine tissues all over the body. Mucous membranes are thus furnished with secretory antibodies in an integrated way, ensuring a variety of specificities at every secretory effector site. There is currently great interest in exploiting this integrated or "common" mucosal immune system for oral vaccination against pathogenic infectious agents and also to induce tolerance in T cell-mediated autoimmune diseases. However, much remains to be learned about mechanisms for antigen uptake and processing necessary to elicit stimulatory or suppressive mucosal immune responses. Moreover, evidence is emerging for the existence of considerable regionalization with regard to functional links between inductive sites and effecter sites of mucosal immunity.

Animals↗

PubMed2003

Regulation of eosinophil migration and Th2 cell function by IL-5 and eotaxin.

Asthma is characterized by elevated production of IgE, Th2 cytokines, chemokines, mucus hypersecretion, globlet cell metaplasia/hyperplasia, airway obstruction, eosinophilia and enhanced bronchial hyperresponsiveness. These hallmark features of asthma have all been linked to the effector functions of Th2 cytokines (e.g., interleukin-(IL)-4,5,9,10, and 13) in clinical and experimental investigations. This article will detail some of the pathogenic effects regulated by IL-13, IL-5 and the eotaxin subfamily of chemokines to regulate certain aspects of allergic disease. In particular, the potency of IL-13 in inducing enhanced bronchial responsiveness to spasmogenic stimuli and mucus hypersecretion suggests a key role of this molecule in the induction of airways obstruction. Recent studies also indicate that IL-5 and eotaxin, through eosinophils, may regulate Th2 cell function and IL-13 production from this lymphocyte. Therefore, IL-5 and IL-13 signaling systems are not necessarily mutually exclusive effector mechanisms, but may also be integrated through eosinophils to regulate certain aspects of allergic diseases. Blocking IL-13, or pathways that may promote IL-13-associated allergic lung responses (IL-5 and eotaxin) could provide an important strategy to improve the specificity of asthma therapy.

Animals↗

PubMed1985

Survival of pathogenic organisms in immunocompetent hosts.

Pathogens have evolved highly individual means of immune evasion. These involve their location within relatively shielded sites, the variability shedding or disguise of surface antigens and modifications of the host immune response. The latter include the use of proteases to split surface-bound antibodies, the production of compounds which consume complement, the avoidance of phagocytosis or the evasion of lysosomal systems of phagocytes and the excretion of products which inactivate effector functions of specific host cell populations. The continued study of immune evasion will enhance understanding of parasitism and promote the means for controlling organisms which are important pathogens of man and domestic animals.

Animals↗

PubMed2004

Contribution of the major secreted yops of Yersinia enterocolitica O:8 to pathogenicity in the mouse infection model.

Pathogenic yersiniae (Yersinia pestis, Y. pseudotuberculosis, and Y. enterocolitica) harbor a 70-kb virulence plasmid (pYV) that encodes a type III secretion system and a set of at least six effector proteins (YopH, YopO, YopP, YopE, YopM, and YopT) that are injected into the host cell cytoplasm. Yops (Yersinia outer proteins) disturb the dynamics of the cytoskeleton, inhibit phagocytosis by macrophages, and downregulate the production of proinflammatory cytokines, which makes it possible for yersiniae to multiply extracellularly in lymphoid tissue. Y. enterocolitica serotype O:8 belongs to the highly mouse-pathogenic group of yersiniae in contrast to Y. enterocolitica serotype O:9. However, there has been no systematic study of the contribution of Yops to the pathogenicity of Y. enterocolitica O:8 in mice. We generated a set of yop gene deletion mutants of Y. enterocolitica O:8 by using the novel Red cloning procedure. We subsequently analyzed the contribution of yopH, -O, -P, -E, -M, -T, and -Q deletions to pathogenicity after oral and intravenous infection of mice. Here we showed for the first time that a DeltayopT deletion mutant colonizes mouse tissues to a greater extent than the parental strain. The DeltayopO, DeltayopP, and DeltayopE mutants were only slightly attenuated after oral infection since they were still able to colonize the spleen and liver and cause systemic infection. The DeltayopO mutant was lethal for mice, whereas DeltayopP and DeltayopE mutants were successfully eliminated from the spleen and liver 2 weeks after infection. In contrast the DeltayopH, DeltayopM, and DeltayopQ mutants were highly attenuated and not able to colonize the spleen and liver on any of the days tested. The DeltayopH, DeltayopO, DeltayopP, DeltayopE, DeltayopM, and DeltayopQ mutants had only modest defects in the colonization of the small intestine and Peyer's patches. The DeltayopE mutant was eliminated from the small intestine 3 weeks after infection, whereas the DeltayopH, DeltayopP, DeltayopM, and DeltayopQ mutants continued to colonize the small intestine at this time.

Administration, Oral↗

PubMed2006

Branched-chain amino acids and immunity.

Although there has been great interest in the effects of amino acids on immune function, little is known about the impact of changes in BCAA availability on the ability of the immune system to function. Human immune cells incorporate BCAA into proteins and are able to oxidize BCAA. The immune system exists to protect the host from pathogenic invaders and from other noxious insults. Upon infection, there is a marked increase in demand for substrates by the immune system; these substrates provide energy and are the precursors for the synthesis of new cells, effector molecules, and protective molecules. Cell culture studies show that BCAA are absolutely essential for lymphocytes to synthesize protein, RNA, and DNA and to divide in response to stimulation. In mice, dietary BCAA restriction impairs several aspects of the immune function and increases the susceptibility to pathogens. Postsurgical or septic patients given BCAA intravenously showed improved immunity and this may relate to improved outcome. BCAAs are therefore absolutely essential for lymphocyte responsiveness and are necessary to support other immune cell functions. However, many aspects of BCAA and its effects on immune function have been understudied or not studied at all. More research is needed to understand the extent of the immune system's requirement for BCAA. It is likely that the essentiality of BCAA for the function of immune cells relates to protein synthesis.

Amino Acids, Branched-Chain↗

PubMed2003

Nucleotide sequence, functional characterization and evolution of pFKN, a virulence plasmid in Pseudomonas syringae pathovar maculicola.

Pseudomonas syringae pv. maculicola strain M6 (Psm M6) carries the avrRpm1 gene, encoding a type III effector, on a 40 kb plasmid, pFKN. We hypothesized that this plasmid might carry additional genes required for pathogenesis on plants. We report the sequence and features of pFKN. In addition to avrRpm1, pFKN carries an allele of another type III effector, termed avrPphE, and a gene of unknown function (ORF8), expression of which is induced in planta, suggesting a role in the plant-pathogen interaction. The region of pFKN carrying avrRpm1, avrPphE and ORF8 exhibits several features of pathogenicity islands (PAIs). Curing of pFKN (creating Psm M6C) caused a significant reduction in virulence on Arabidopsis leaves. However, complementation studies using Psm M6C demonstrated an obvious virulence function only for avrRpm1. pFKN can integrate and excise from the chromosome of Psm M6 at low frequency via homologous recombination between identical sequence segments located on the chromosome and on pFKN. These segments are part of two nearly identical transposons carrying avrPphE. The avrPphE transposon was also detected in other strains of P. s. pv. maculicola and in P. s. tomato strain DC3000. The avrPphE transposon was found inserted at different loci in different strains. The analysis of sequences surrounding the avrPphE transposon insertion site in the chromosome of Psm M6 indicates that pFKN integrates into a PAI that encodes type III effectors. The integration of pFKN into this chromosomal region may therefore be seen as an evolutionary process determining the formation of a new PAI in the chromosome of Psm M6.

Arabidopsis↗

PubMed1999

Activation of the CDC42 effector N-WASP by the Shigella flexneri IcsA protein promotes actin nucleation by Arp2/3 complex and bacterial actin-based motility.

To propel itself in infected cells, the pathogen Shigella flexneri subverts the Cdc42-controlled machinery responsible for actin assembly during filopodia formation. Using a combination of bacterial motility assays in platelet extracts with Escherichia coli expressing the Shigella IcsA protein and in vitro analysis of reconstituted systems from purified proteins, we show here that the bacterial protein IcsA binds N-WASP and activates it in a Cdc42-like fashion. Dramatic stimulation of actin assembly is linked to the formation of a ternary IcsA-N-WASP-Arp2/3 complex, which nucleates actin polymerization. The Arp2/3 complex is essential in initiation of actin assembly and Shigella movement, as previously observed for Listeria monocytogenes. Activation of N-WASP by IcsA unmasks two domains acting together in insertional actin polymerization. The isolated COOH-terminal domain of N-WASP containing a verprolin-homology region, a cofilin-homology sequence, and an acidic terminal segment (VCA) interacts with G-actin in a unique profilin-like functional fashion. Hence, when N-WASP is activated, its COOH-terminal domain feeds barbed end growth of filaments and lowers the critical concentration at the bacterial surface. On the other hand, the NH(2)-terminal domain of N-WASP interacts with F-actin, mediating the attachment of the actin tail to the bacterium surface. VASP is not involved in Shigella movement, and the function of profilin does not require its binding to proline-rich regions.

Actin-Related Protein 2↗

PubMed1990

In defense of mucosal surfaces. Development of novel vaccines for IgA responses protective at the portals of entry of microbial pathogens.

A common mucosal immune system occurs in mammalian species, where antigen stimulation of BALT and GALT induces an exodus of specific lymphocytes that home to the various mucosal effector sites. These responses are finely regulated and T cells and cytokines are of central importance for ultimate plasma cell differentiation and for production of S-IgA antibodies in our external secretions. The current need for vaccines, including those to respiratory, gastrointestinal, and genitourinary tract infections as well as the universal efforts to develop immunity to HIV and AIDS, compels us to continue to better understand how we can use the common mucosal immune system to advantage for eventual prevention of infectious diseases. This article summarizes the various antigen delivery strategies and progress of oral vaccines for induction of protective mucosal immune responses to various viral and bacterial diseases.

Administration, Oral↗

PubMed1998

Type III protein secretion systems in plant and animal pathogenic bacteria.

Among many interesting and sophisticated mechanisms used by bacterial pathogens to subvert eukaryotic hosts is a class of specialized protein secretion systems (known as type III protein secretion systems) that deliver bacterial virulence proteins directly into the host cell. Recent studies have revealed four important features of these secretion systems. First, they are widespread among plant and animal bacterial pathogens, and mutations affecting type III protein secretion often eliminate bacterial virulence completely. Second, at least eight type III secretion components share sequence similarities with those of the flagellar assembly machinery and flagellum-like structures are associated with type III secretion, raising the possibility that these secretion systems are derived from the presumably more ancient flagellar assembly apparatus. Third, type III secretion is activated in vivo upon contact with host cells. Fourth, the type III secretion mechanism is Sec-independent and the effector proteins may possess mRNA-based targeting signals. This review highlights the similarities and differences among type III secretion systems of selected model plant and animal pathogenic bacteria.

Journal Article↗

PubMed2006

Abrogation of functional selectin-ligand expression reduces migration of pathogenic CD8+ T cells into heart.

CD8+ T cells are involved in autoimmune and infectious myocarditis and cardiac allograft rejection. The role of selectins in cardiac recruitment of CD8+ T cells is not understood. In this study, the contribution of T cell selectin ligands to effector CD8+ T cell recruitment into the heart was examined using a model of myocarditis, which depends on transfer of OVA peptide-specific CD8+ T cells (OT-I) into mice (CMy-mOva) that express OVA in the heart. alpha-(1,3)-Fucosyltransferase (FucT)-VII-deficient OT-I cells displayed over a 95% reduction in their ability to interact with P-selectin under flow conditions in vitro, compared with wild-type OT-I cells. Interaction of FucT-VII-deficient OT-I cells with E-selectin was reduced approximately 50%. FucT-VII-deficient OT-I cells were also less efficiently recruited into a dermal site of Ag and adjuvant injection. Significantly, FucT-VII-deficient OT-I cells were also impaired in their ability to migrate into CMy-mOva hearts, compared with wild-type OT-I cells. Transfer of FucT-VII-deficient T cells caused less severe early myocarditis and myocyte damage than transfer of wild-type T cells. Combined FucT-IV/VII-deficient OT-I cells displayed a more profound reduction in E-selectin interactions in vitro compared with FucT-VII-deficient T cells, and the FucT-IV/VII-deficient T cells also showed less early recruitment and pathogenicity in the CMy-mOva myocarditis model. These results identify a prominent role for selectin ligands in contributing to effector CD8+ T cell recruitment into the myocardium and indicate that selectin-dependent T cell recruitment is relevant to other tissues besides the skin.

Adoptive Transfer↗

PubMed2003

'Order from disorder sprung': recognition and regulation in the immune system.

Milton's epic poem Paradise lost supplies a colourful metaphor for the immune system and its responses to pathogens. With the role of Satan played by pathogens seeking to destroy the paradise of human health, GOD intervenes and imposes order out of chaos. In this context, GOD means 'generation of diversity': the capacity of the innate and specific immune responses to recognize and eliminate a universe of pathogens. Thus, the immune system can be thought of as an entity that self-assembles the elements required to combat bodily invasion and injury. In so doing, it brings to bear the power of specific recognition: the ability to distinguish self from non-self, and the threatening from the benign. This ability to define and protect self is evolutionarily very old. Self-recognition and biochemical and barrier defences can be detected in primitive organisms, and elements of these mechanisms are built upon in an orderly way to establish the mammalian immune system. Innate immune responses depend on the use of a limited number of germline-encoded receptors to recognize conserved molecular patterns that occur on the surfaces of a broad range of pathogens. The B and T lymphocytes of the specific immune response use complex gene-rearrangement machinery to generate a diversity of antigen receptors capable of recognizing any pathogen in the universe. Binding to receptors on both innate and specific immune-system cells triggers intricate intracellular signalling pathways that lead to new gene transcription and effector-cell activation. And yet, regulation is imposed on these responses so that Paradise is not lost to the turning of the immune system onto self-tissues, the spectre of autoimmunity. Lymphocyte activation requires multiple signals and intercellular interactions. Mechanisms exist to establish tolerance to self by the selection and elimination of cells recognizing self-antigens. Immune system cell populations are reduced by programmed cell death once the pathogen threat is resolved. Once Paradise has been regained, memory cells remain in the body to sharply reduce the impact of a second exposure to a pathogen. Vaccination programs take advantage of this capacity of the human immune system for immunological memory, sparing millions the suffering associated with disease scourges. Thus does the order of the immune response spring from the disorder of pathogen attacks, and thus is Paradise preserved.

Adaptation, Physiological↗

PubMed2025

Barley resistance and susceptibility to fungal cell entry involve the interplay of ROP signaling with phosphatidylinositol-monophosphates.

Rho-of-plant small GTPases (ROPs) are regulators of plant polar growth and of plant-pathogen interactions. The barley ROP, RACB, is involved in susceptibility toward infection by the barley powdery mildew fungus Blumeria hordei (Bh) but little is known about the cellular pathways that connect RACB signaling to disease susceptibility. Here we identify novel RACB interaction partners of plant or fungal origin by untargeted co-immunoprecipitation of constitutively active (CA) RACB tagged by green fluorescent protein from Bh-infected barley epidermal layers and subsequent analysis by liquid chromatography-coupled mass spectrometry. Three of the immunoprecipitated proteins, a plant phosphoinositide phosphatase, a plant phosphoinositide phospholipase, and a putative Bh-effector protein, are involved in the barley-Bh-pathosystem and support disease resistance or susceptibility, respectively. RACB and its plant interactors bind to overlapping anionic phospholipid species in vitro, and in the case of RACB, this lipid interaction is mediated by its carboxy-terminal polybasic region (PBR). Fluorescent markers for anionic phospholipids show altered subcellular distribution in barley cells during Bh attack and under expression of a RACB-binding fungal effector. Phosphatidylinositol 4-phosphate, phosphatidylinositol 3,5-bisphosphate, and phosphatidylserine show a distinct enrichment at the haustorial neck region, suggesting a connection to subcellular targeting of RACB at this site. The interplay of ROPs with anionic phospholipids and phospholipid-metabolizing enzymes may thus enable the subcellular enrichment of components pivotal for success or failure of fungal penetration.

Hordeum↗

PubMed2001

A key role for ICAM-1 in generating effector cells mediating inflammatory responses.

We investigated how the accessory molecule interactions encountered during T cell priming influence T cell-mediated destruction of insulin-producing beta cells and lead to type 1 diabetes. T cell receptor (TCR)-transgenic CD4+ T cells were primed under controlled conditions in vitro before being adoptively transferred into transgenic recipients expressing membrane ovalbumin under the control of the rat insulin promoter (RIP-mOVA). During priming, antigen-presenting cell expression of B7-1 without intracellular adhesion molecule 1 (ICAM-1) led to the generation of effector cells that migrated to the pancreata of RIP-mOVA recipients but did not cause diabetes. In contrast, when T cells were primed with APCs expressing both B7-1 and ICAM-1, pronounced destruction of beta cells and a rapid onset of diabetes were observed. Pathogenicity was associated with T cell production of the macrophage-attracting chemokines CCL3 and CCL4. Thus, interactions of lymphocyte function-associated antigen 1 with ICAM-1 during priming induce both qualitative and quantitative alterations in T effector function and induce potentially autodestructive responses.

Animals↗

PubMed1998

Identification of a pathogenicity island required for Salmonella enteropathogenicity.

Salmonella spp. interact with ileal mucosa and disrupt normal intestinal function, which results in an acute inflammatory cell influx, fluid secretion and enteritis. We have recently characterized SopB, a novel secreted effector protein of Salmonella dublin, and presented evidence that SopB is translocated into eukaryotic cells via a sip-dependent pathway to promote fluid secretion and inflammatory responses. Here, we show that sopB is located on a large DNA fragment unique to the Salmonella chromosome. This locus is conserved in Salmonella and maps at approximately 20 centisome of the S. typhimurium chromosome. Sequence analysis revealed that this Salmonella-specific DNA fragment is flanked by DNA sequences with significant sequence similarity to the Escherichia coli K-12 genes, tRNA1ser (serT) on one side and copS/copR on the other. Thus, this Salmonella-specific DNA fragment has features characteristic of 'pathogenicity islands' and, therefore, it was denoted SPI-5 (Salmonella pathogenicity island-5). SPI-5 was sequenced and was found to contain five novel genes, pipA, pipB, pipC, pipD (pathogenicity island-encoded proteins) and orf, in addition to sopB. The effect of mutations in pipA, pipB and pipD on the induction of fluid secretion and an acute inflammatory cell influx was assessed in bovine ligated ileal loops. The effect of mutations in SPI-5-encoded genes on systemic salmonellosis was assessed in mice. The results of these experiments suggest that SPI-5-encoded genes contribute to enteric but not to systemic salmonellosis.

Amino Acid Sequence↗

PubMed2005

Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T-cells.

Diabetogenic T-cells can be detected in pre-diabetic nonobese diabetic (NOD) mice after transfer in NOD-SCID recipients. Here we demonstrate that 6-week-old pre-diabetic NOD mice, >2 months before disease onset, already harbor pathogenic T-cells in equal numbers to overtly diabetic animals. The delay in diabetes appearance is explained by the presence of regulatory CD4+ CD25+ T-cells that control diabetogenic effectors and that are, in our hands, transforming growth factor (TGF)-beta-dependent. Our present results suggest, however, that diabetes onset is only partly explained by a decline in this regulatory T-cell activity. Another major factor appears to be the progressive resistance of diabetogenic cells to TGF-beta-dependent mediated inhibition. We propose that progression to overt disease correlates with the pathogenic T-cell's escape from TGF-beta-dependent T-cell-mediated regulation.

Adoptive Transfer↗