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Results for “toxin secretion system”

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At least 307 records · Page 17Linked to original sources

PubMed2004

TGF-beta receptor signaling is critical for mucosal IgA responses.

TGF-beta receptor (TbetaR) signaling is important for systemic IgA production; however, its contribution to IgA secretion at mucosal sites remained uncertain. This important question was addressed using mice lacking the TbetaR in B cells (TbetaRII-B). Although reduced, IgA-secreting cells and IgA were still present in the systemic and mucosal compartments. The adaptive immune response was investigated after oral or nasal immunization using adjuvants acting on different molecular targets, namely, the cholera toxin B subunit and the macrophage-activating lipopeptide-2. Efficient Ag-specific cellular and humoral responses were triggered both in controls and TbetaRII-B mice. However, a significant reduction in Ag-specific IgG2b and increased levels of IgG3 were observed in sera from TbetaRII-B mice. Furthermore, Ag-specific IgA-secreting cells, serum IgA, and secretory IgA were undetectable in TbetaRII-B mice. These results demonstrate the critical role played by TbetaR in Ag-driven stimulation of secretory IgA responses in vivo.

Administration, Intranasal↗

PubMed2006

Type IV secretion systems and their effectors in bacterial pathogenesis.

Type IV secretion systems (T4SSs) are membrane-associated transporter complexes used by various bacteria to deliver substrate molecules to a wide range of target cells. T4SSs are involved in horizontal DNA transfer to other bacteria and eukaryotic cells, in DNA uptake from or release into the extracellular milieu, in toxin secretion and in the injection of virulence factors into eukaryotic host target cells by several mammalian pathogens. Rapid progress has been made towards defining the structures and functions of T4SSs, identifying the translocated effector molecules and elucidating the mechanisms by which the effectors subvert eukaryotic cellular processes during infection. These findings have had an important impact on our understanding of how these pathogens manipulate host cell functions to trigger bacterial uptake, facilitate intracellular growth and suppress defence mechanisms, thus facilitating bacterial colonization and disease development.

Animals↗

PubMed1996

Relationship between cAMP induced inhibition of human meningioma cell proliferation and autocrine secretion of interleukin-6.

Previous studies have suggested that activation of the adenylyl cyclase - cAMP system in meningiomas results in decreased mitosis. We have used meningioma cell culture to further investigate this phenomenon and to examine the potential role played by interleukin-6 (IL6). Incubation of cultured meningioma cells for 4-6 days with cholera toxin and theophylline, both of which increase intracellular cAMP levels, markedly stimulated IL6 secretion and inhibited cell growth rate. Similar effects were observed with 8-bromo-cAMP. In contrast, a neutralising polyclonal antibody against IL6 significantly stimulated meningioma proliferation and reduced the inhibitory effects of 8-bromo-cAMP. These results support the concept that IL6 acts as an autocrine / paracrine inhibitory factor for meningioma proliferation, and that the inhibition exerted by elevated intracellular cAMP levels may be at least partially mediated via increased secretion of the cytokine.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2004

Development of neuronal sensitivity to toxins in cerebrospinal fluid from HIV-type 1-infected individuals.

HIV infection of the immature nervous system generally results in a rapid progression of neurological disease that cannot easily be explained by the severity of encephalitis, viral burden, systemic immune deficiency, or developmental changes in utero. Rather than the viral infection dictating disease progression, we explored the possibility that immature neurons might be particularly sensitive to toxins secreted in response to HIV. Primary cultures of rat cortical neurons were exposed to toxic cerebrospinal fluid (CSF) from HIV-infected individuals (CSF(tox)) and evaluated for changes in intracellular calcium and cell death. CSF(tox) had no detectable effect on early neurite outgrowth, calcium regulation, or cell death during the first few days in culture. Starting at Day 4, delayed increases in intracellular calcium appeared in response to CSF(tox). The magnitude of the delayed calcium rise and cell death increased with the age of the culture and correlated with the appearance of synaptophysin immunoreactive varicosities. A similar gradual development of sensitivity was seen during exposure of feline neurons to toxins generated by choroid plexus macrophages after exposure to feline immunodeficiency virus. The possibility that toxin sensitivity is dependent on the presence of synaptic activity is consistent with the rapid pathogenesis in the CNS seen during the first postnatal year. Emerging synaptic activity coupled with other factors such as high metabolic demand in the young nervous system may combine to increase the likelihood of calcium overload and neuronal dysfunction in response to HIV-associated toxins.

Animals↗

PubMed1992

E. coli hemolysin interactions with prokaryotic and eukaryotic cell membranes.

The hemolysin toxin (HlyA) is secreted across both the cytoplasmic and outer membranes of pathogenic Escherichia coli and forms membrane pores in cells of the host immune system, causing cell dysfunction and death. The processes underlying the interaction of HlyA with the bacterial and mammalian cell membranes are remarkable. Secretion of HlyA occurs without a periplasmic intermediate and is directed by an uncleaved C-terminal targetting signal and the HlyB and HlyD translocator proteins, the former being a member of a transporter superfamily central to import and export of a wide range of substrates by prokaryotic and eukaryotic cells. The separate process by which HlyA is targetted to mammalian cell membranes is dependent upon fatty acylation of a non-toxic precursor, proHlyA. This is achieved by a novel mechanism directed by the activator protein HlyC, which binds to an internal proHlyA recognition sequence and provides specificity for the transfer of fatty acid from cellular acyl carrier protein.

Acylation↗

PubMed1996

Production of diarrheal toxin by selected strains of Bacillus cereus.

The production of diarrheal toxin by six selected strains of Bacillus cereus was monitored during growth at 32 degrees C, a temperature described as near-optimal for growth and toxin production. Toxic activity was measured in culture filtrates and cellular extracts sampled at three different times during growth. Two alternative methods, a cytotoxicity test on Chinese hamster ovary (CHO) cells and a commercial immunological test (BCET-RPLA, Oxoid) were used. Toxin titres were in agreement with epidemiological characteristics and toxicity demonstrated by using other systems in other examinations. A comparison of intra- and extracellular toxicities measured at the exponential and stationary growth phases showed that the toxin was essentially secreted during the exponential phase. For several strains, secretion peaked during the period from the middle exponential phase to the beginning of the stationary phase. There was no important overall increase of the toxicity during full and late stationary phase. The level was stable or even lower, thus indicating that diarrheal toxin production during stationary phase was small, if any, and that the toxin was unstable under these conditions. Statistical analysis of toxicities showed that the cytotoxicity test was correlated with the immunological test (significant at a 1% level). For routine determinations, a toxicologic laboratory may use any of the two methods, depending on its facilities, the immunological test being relatively expensive.

Animals↗

PubMed2001

Biology of type II secretion.

The type II secretion pathway or the main terminal branch of the general secretion pathway, as it has also been referred to, is widely distributed among Proteobacteria, in which it is responsible for the extracellular secretion of toxins and hydrolytic enzymes, many of which contribute to pathogenesis in both plants and animals. Secretion through this pathway differs from most other membrane transport systems, in that its substrates consist of folded proteins. The type II secretion apparatus is composed of at least 12 different gene products that are thought to form a multiprotein complex, which spans the periplasmic compartment and is specifically required for translocation of the secreted proteins across the outer membrane. This pathway shares many features with the type IV pilus biogenesis system, including the ability to assemble a pilus-like structure. This review discusses recent findings on the organization of the secretion apparatus and the role of its various components in secretion. Different models for pilus-mediated secretion through the gated pore in the outer membrane are also presented, as are the possible properties that determine whether a protein is recognized and secreted by the type II pathway.

Animals↗

PubMed1998

Neuropeptide Y2 receptors on nerve endings from the rat neurohypophysis regulate vasopressin and oxytocin release.

Neuropeptide Y and peptide YY are important central and peripheral modulators of cardiovascular and neuroendocrine functions, that act through multiple receptor subtypes, Y1 through Y5. A neuropeptide Y-binding site of the Y2 type was characterized by ligand-binding studies in isolated nerve terminals from the rat neurohypophysis. Functionally, neuropeptide Y and peptide YY dose-dependently triggered arginine 8-vasopressin and oxytocin release from perfused isolated terminals, and potentiated the arginine-8-vasopressin release induced by depolarization. Osmotic stimulation by salt loading of rats for two and seven days caused a more than three-fold increase in the neuropeptide Y content of the nerve endings. However, the Y2 receptor expression and arginine-8-vasopressin content declined, showing that the neuropeptide Y system is dynamic and suggesting that it plays a physiological role in salt and water homeostasis. Two sets of observations suggest the arginine-8-vasopressin release by neuropeptide Y may not be explained by neuropeptide Y effects on intracellular Ca2+. First, absence of Ca2+ from the perfusion medium did not affect the arginine-8-vasopressin release, and secondly neuropeptide Y did not change intraterminal Ca2+ concentrations. Pretreatment with pertussis toxin blocked arginine-8-vasopressin secretion by neuropeptide Y, suggesting activation of Gi or Go heterotrimeric G-proteins are required for secretion. It is concluded, that the nerve endings of the neurohypophysis contain a complete neuropeptide Y system with ligand and receptors. Neuropeptide Y may act in an autocrine fashion via activation of Y2 neuropeptide Y receptors to stimulate the release of vasopressin and oxytocin via a Gi/Go dependent secretory mechanism.

Animals↗

PubMed1999

Intranasal immunization with heat-inactivated Streptococcus pneumoniae protects mice against systemic pneumococcal infection.

In order to study the mucosal and serum antibody response to polysaccharide-encapsulated bacteria in mice, a preparation of heat-inactivated Streptococcus pneumoniae type 4 was administered, with and without cholera toxin, at various mucosal sites. It appeared that intranasal immunization of nonanesthesized animals was superior to either oral, gastric, or colonic-rectal antigen delivery with regard to the induction of serum immunoglobulin G (IgG) and IgA, as well as saliva IgA antibodies specific for pneumococci. The marked IgA antibody response in feces after intranasal, but not after oral or gastric, immunization is suggestive of a cellular link between the nasal induction site and the distant mucosal effector sites. Intranasal immunization also induced antibodies in serum and in mucosal secretions against type-specific capsular polysaccharide. IgA and IgG antibody levels in pulmonary lavage fluids correlated well with saliva IgA and serum IgG antibodies, respectively. Antibody determinations in pulmonary secretions may therefore be redundant in some cases, and the number of experimental animals may be reduced accordingly. After intraperitoneal challenge with type 4 pneumococci, mice immunized intranasally were protected against both systemic infection and death, even without the use of cholera toxin as a mucosal adjuvant. Thus, an efficient intranasal vaccine against invasive pneumococcal disease may be based on a very simple formulation with whole killed pneumococci.

Administration, Intranasal↗

PubMed1992

A new model of human secretory diarrhoea using cholera toxin.

Secretory diarrhoea is a major cause of morbidity and mortality worldwide. However, there is no biologically relevant test system in man for assessing new anti-diarrhoeal therapies prior to clinical trial. We have used highly purified cholera toxin in combination with the triple lumen jejunal perfusion technique to establish a subclinical model of cholera in man. Cholera toxin was administered either by mouth with sodium bicarbonate or directly into a 30 cm 'open' or 'closed' (isolated between two inflated balloons) jejunal segment in healthy adult volunteers. Both oral dosing and direct delivery into an 'open' jejunal segment failed to produce consistent secretion of water and electrolytes. In contrast 15 micrograms or 25 micrograms of cholera toxin elicited secretion of water and sodium 3 h after instillation into the balloon occluded 'closed' jejunal segment (P less than 0.05 vs. controls). The rate of secretion was constant over the maximal period studied (4.5 h) and was similar to that reported in human cholera. None of the subjects experienced troublesome diarrhoea. We believe this model offers a relevant test system for assessing anti-diarrhoeal therapy in man.

Administration, Oral↗

PubMed2000

Enterotoxins and the enteric nervous system--a fatal attraction.

Although there has been extensive investigation of the biochemical consequences of the interactions between bacterial enterotoxins and intestinal epithelial cells and the mechanisms by which they induce intestinal secretion, relatively little attention has been given to other aspects of the host response to these enterotoxins. There is now compelling evidence that the enteric nervous system has a major role in enhancing the secretory state induced by cholera toxin, the E. coli enterotoxins and possibly C. difficile toxin A. Cholera toxin for example is thought to activate a neural reflex via the release of 5-hydroxytryptamine from enterochromaffin cells. Neurotransmitters involved in the reflex include substance P and vasoactive intestinal polypeptide. Delineation of these neural pathways may offer new possibilities for the pharmacological control of enterotoxin-mediated secretion.

Animals↗

PubMed2001

Effects of phosphotyrosine phosphatase inhibition on insulin secretion and intracellular signaling events in rat pancreatic islets.

Isolated rat pancreatic islets were incubated at 3.3 (low) and 16.7 (high) mM glucose with different concentrations of the phosphotyrosine phosphatase (PTP) inhibitor, peroxovanadate (pV). At low glucose, pV stimulated insulin secretion 2- to 4-fold, but it inhibited insulin secretion at 16.7 mM. The latter effect was not due to an inhibition of glucose metabolism, nor was it inhibited by pertussis toxin pretreatment. In addition, pV stimulated insulin secretion approximately 3-fold in depolarized cells at both low and high glucose. pV markedly increased the tyrosine phosphorylation of several proteins, including IRS-1 and -2, and also increased the phosphorylation of the downstream kinases PKB/Akt and MAPK. PKB/Akt, but not MAPK, was also phosphorylated in the absence of pV. Intracellular pV-stimulated tyrosine phosphorylation, including that of IRS-2, was generally increased by high glucose suggesting a further inhibition of PTP and/or enhanced tyrosine kinase activity. Thus, these data suggest that intracellular tyrosine and serine (PKB/Akt) phosphorylation are related to insulin secretion but they do not support a unique and direct link between IRS-2 tyrosine phosphorylation and glucose-stimulated insulin secretion.

Animals↗

PubMed1982

Immunological cross-reactivity of enterotoxins of Aeromonas hydrophila and cholera toxin.

Pre-incubation with anticholera toxin (ACT) significantly reduced intestinal secretion induced by cell-free broth preparations of heat-labile toxins (LT) of Escherichia coli and Aeromonas hydrophila in jejunal perfusion experiments in rats in vivo. Pre-incubation with ACT also prevented cytotoxicity by E. coli LT in the Y1 cell culture system. Pre-incubation had no effect on cytotoxicity in Y1 and L132 cell lines or on haemolytic activity with cell-free preparations of A. hydrophila. In another series of experiments rats were immunized with cholera toxin given as an intraperitoneal priming dose followed 12 days later by intraduodenal boosting. Immunization significantly protected against net intestinal fluid secretion induced by enterotoxigenic E. coli and A. hydrophila and by cholera toxin.

Aeromonas↗

PubMed1996

Salivary, nasal, genital, and systemic antibody responses in monkeys immunized intranasally with a bacterial protein antigen and the Cholera toxin B subunit.

Previous attempts to induce mucosal antibodies in rhesus monkeys by enteric immunization have resulted in only modest and short-lived responses, dominated by immunoglobulin M (IgM) antibodies in the plasma. In this study, two groups of rhesus monkeys were immunized intranasally three times at 2-week intervals with a bacterial protein antigen (AgI/II) either chemically coupled to or mixed with the B subunit of cholera toxin (CT), a known potent mucosal immunogen and carrier for other immunogens. Cells secreting antibodies, predominantly of the IgA isotype, to AgI/II and to CT were detected in the peripheral blood 1 week after each immunization, indicating the dissemination of IgA-secreting precursor cells through the mucosal immune system. IgG and, to a lesser extent, IgA antibodies to both proteins were induced in the plasma commencing after the second immunization. Plasma IgE concentrations and IgE antibody levels were not consistently raised during the immunization period. IgA antibodies were found in nasal and vaginal washes. Nasal IgG but not IgA antibodies showed a significant positive correlation with plasma IgG antibody levels, suggesting that they were largely derived by transudation from the circulation. Analysis of the molecular form of vaginal IgA indicated that both secretory and monomeric forms of IgA were present in various proportions. Furthermore, neither IgG nor IgA antibodies in vaginal washes were correlated with plasma antibody responses, suggesting the contribution of locally synthesized antibodies of both isotypes. Comparison of the responses between the two groups of animals showed only sporadic significant differences, indicating that intranasal immunization with AgI/II either coupled to or mixed with the B subunit of CT was equally effective at inducing generalized IgA antibody responses in the mucosal immune system and predominantly IgG antibodies in the plasma.

Administration, Intranasal↗

PubMed1988

[Killer systems of Saccharomyces cerevisiae yeasts].

The killer systems of Saccharomyces cerevisiae are a peculiar group of cytoplasmic symbionts of primitive eukaryotes. The genetic material of these symbionts is double-stranded RNA. Their basic properties are linearity of genome, its fragmentation, resulting in two separately replicating major and minor segments, and the ability to control the synthesis of secretory proteins--mycocins which can kill the taxonomically related strains. Secretion of mycocins also confers immunity to their action. The strains containing killer symbionts are toxigenic and resistant to their own toxins, while those with no killer double-stranded RNA are sensitive to mycocins. The killer systems of Saccharomyces cerevisiae possess some properties relevant to viruses and evidently are evolved during the evolution of infectious viruses. Occurrence of such systems in monocellular eucaryotic organisms is an example of genome complication in the course of putting together the virus-like components. The peculiarities of replication and expression of killer systems and their utilization for the construction of vector molecules are discussed.

Cytoplasm↗

PubMed1997

Transcriptional analysis of the divergent cagAB genes encoded by the pathogenicity island of Helicobacter pylori.

Helicobacter pylori strains isolated from most patients with peptic ulcer disease and adenocarcinoma express the vacuolating toxin VacA and contain a pathogenicity island named cag. The cag pathogenicity island codes for more than 40 putative proteins with features similar to bacterial secretion systems. One of these proteins, CagA, is an immunodominant antigen with unknown function encoded by the cagA gene. In the present study, we have analysed the functional promoter elements of the H. pylori cagA gene as well as of the divergently transcribed cagB gene. Primer extension analyses identified a single 5' end of the cagA mRNA, while two initiation sites were mapped in the case of the cagB mRNA. The promoters deduced upstream of these start points of transcription contained conserved -10 regions but no -35 regions with respect to the Escherichia coli sigma70 consensus sequence. Nevertheless, they could be activated in E. coli and in vitro by purified E. coli RNA polymerase. Deletion analyses indicated that the cagA and cagB genes are transcribed by overlapping promoters and that full activation requires sequences up to -70 and -96 respectively. Instead, basal transcription is likely to be mediated by -10 extended promoter-like sequences. RNA polymerase is able to bind the -40 to -60 region of the cagA promoter, and its binding is mediated by the alpha-subunit. This region resembles the UP elements of prokaryotic promoters in location, sequence and mechanism of interaction with the RNA polymerase. We discuss the features of these promoters and propose that they could represent a class of minimum promoters, which ensures a basic level of transcription, while full activation requires regulatory elements or a defined promoter context.

Antigens, Bacterial↗

PubMed2006

A C-terminal domain targets the Pseudomonas aeruginosa cytotoxin ExoU to the plasma membrane of host cells.

ExoU, a phospholipase injected into host cells by the type III secretion system of Pseudomonas aeruginosa, leads to rapid cytolytic cell death. Although the importance of ExoU in infection is well established, the mechanism by which this toxin kills host cells is less clear. To gain insight into how ExoU causes cell death, we examined its subcellular localization following transfection or type III secretion/translocation into HeLa cells. Although rapid cell lysis precluded visualization of wild-type ExoU by fluorescence microscopy, catalytically inactive toxin was readily detected at the periphery of HeLa cells. Biochemical analysis confirmed that ExoU was targeted to the membrane fraction of transfected cells. Visualization of ExoU peptides fused with green fluorescent protein indicated that the domain responsible for this targeting was in the C terminus of ExoU, between residues 550 and 687. Localization to the plasma membrane occurred within 1 h of expression, which is consistent with the kinetics of cytotoxicity. Together, these results indicate that a domain between residues 550 and 687 of ExoU targets this toxin to the plasma membrane, a process that may be important in cytotoxicity.

3T3 Cells↗

PubMed2004

Recent advances in the characterization of ambient pH regulation of gene expression in filamentous fungi and yeasts.

All microorganisms must adapt to the pH of their environment. One aspect of this adaptation, particularly important for organisms that grow over a wide pH range, is the ability to express appropriately genes whose roles ultimately involve functions at the cell surface or in the environment. Genes encoding permeases, secreted enzymes, enzymes involved in synthesis of exported metabolites such as toxins and antibiotics, and probably enzymes modifying secreted proteins posttranslationally all fall into this category. Here we discuss the most recent findings on the transcriptional regulatory system in fungi that enables such genes to be expressed only when the ambient pH is conducive to their ultimate functions. The intriguing issue of how pH is sensed and how the resulting signal is transmitted to the transcription factor involves at least one late endosome component. Proper functioning of the regulatory system responding to ambient pH is essential for fungal pathogenicity of both animals and plants.

Aspergillus nidulans↗