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PubMed1983

Secretion of Saccharomyces cerevisiae killer toxin: processing of the glycosylated precursor.

Killer toxin secretion was blocked at the restrictive temperature in Saccharomyces cerevisiae sec mutants with conditional defects in the S. cerevisiae secretory pathway leading to accumulation of endoplasmic reticulum (sec18), Golgi (sec7), or secretory vesicles (sec1). A 43,000-molecular-weight (43K) glycosylated protoxin was found by pulse-labeling in all sec mutants at the restrictive temperature. In sec18 the protoxin was stable after a chase; but in sec7 and sec1 the protoxin was unstable, and in sec1 11K toxin was detected in cell lysates. The chymotrypsin inhibitor tosyl-l-phenylalanyl chloromethyl ketone (TPCK) blocked toxin secretion in vivo in wild-type cells by inhibiting protoxin cleavage. The unstable protoxin in wild-type and in sec7 and sec1 cells at the restrictive temperature was stabilized by TPCK, suggesting that the protoxin cleavage was post-sec18 and was mediated by a TPCK-inhibitable protease. Protoxin glycosylation was inhibited by tunicamycin, and a 36K protoxin was detected in inhibited cells. This 36K protoxin was processed, but toxin secretion was reduced 10-fold. We examined two kex mutants defective in toxin secretion; both synthesized a 43K protoxin, which was stable in kex1 but unstable in kex2. Protoxin stability in kex1 kex2 double mutants indicated the order kex1 --> kex2 in the protoxin processing pathway. TPCK did not block protoxin instability in kex2 mutants. This suggested that the KEX1- and KEX2-dependent steps preceded the sec7 Golgi block. We attempted to localize the protoxin in S. cerevisiae cells. Use of an in vitro rabbit reticulocyte-dog pancreas microsomal membrane system indicated that protoxin synthesized in vitro could be inserted into and glycosylated by the microsomal membranes. This membrane-associated protoxin was protected from trypsin proteolysis. Pulse-chased cells or spheroplasts, with or without TPCK, failed to secrete protoxin. The protoxin may not be secreted into the lumen of the endoplasmic reticulum, but may remain membrane associated and may require endoproteolytic cleavage for toxin secretion.

Killer Factors, Yeast↗
PubMed2003

The complete genome sequence of the carcinogenic bacterium Helicobacter hepaticus.

Helicobacter hepaticus causes chronic hepatitis and liver cancer in mice. It is the prototype enterohepatic Helicobacter species and a close relative of Helicobacter pylori, also a recognized carcinogen. Here we report the complete genome sequence of H. hepaticus ATCC51449. H. hepaticus has a circular chromosome of 1,799,146 base pairs, predicted to encode 1,875 proteins. A total of 938, 953, and 821 proteins have orthologs in H. pylori, Campylobacter jejuni, and both pathogens, respectively. H. hepaticus lacks orthologs of most known H. pylori virulence factors, including adhesins, the VacA cytotoxin, and almost all cag pathogenicity island proteins, but has orthologs of the C. jejuni adhesin PEB1 and the cytolethal distending toxin (CDT). The genome contains a 71-kb genomic island (HHGI1) and several genomic islets whose G+C content differs from the rest of the genome. HHGI1 encodes three basic components of a type IV secretion system and other virulence protein homologs, suggesting a role of HHGI1 in pathogenicity. The genomic variability of H. hepaticus was assessed by comparing the genomes of 12 H. hepaticus strains with the sequenced genome by microarray hybridization. Although five strains, including all those known to have caused liver disease, were indistinguishable from ATCC51449, other strains lacked between 85 and 229 genes, including large parts of HHGI1, demonstrating extensive variation of genome content within the species.

Cell Movement↗
PubMed2019

Large-scale genome analysis of bovine commensal Escherichia coli reveals that bovine-adapted E. coli lineages are serving as evolutionary sources of the emergence of human intestinal pathogenic strains.

How pathogens evolve their virulence to humans in nature is a scientific issue of great medical and biological importance. Shiga toxin (Stx)-producing Escherichia coli (STEC) and enteropathogenic E. coli (EPEC) are the major foodborne pathogens that can cause hemolytic uremic syndrome and infantile diarrhea, respectively. The locus of enterocyte effacement (LEE)-encoded type 3 secretion system (T3SS) is the major virulence determinant of EPEC and is also possessed by major STEC lineages. Cattle are thought to be the primary reservoir of STEC and EPEC. However, genome sequences of bovine commensal E. coli are limited, and the emerging process of STEC and EPEC is largely unknown. Here, we performed a large-scale genomic comparison of bovine commensal E. coli with human commensal and clinical strains, including EPEC and STEC, at a global level. The analyses identified two distinct lineages, in which bovine and human commensal strains are enriched, respectively, and revealed that STEC and EPEC strains have emerged in multiple sublineages of the bovine-associated lineage. In addition to the bovine-associated lineage-specific genes, including fimbriae, capsule, and nutrition utilization genes, specific virulence gene communities have been accumulated in stx- and LEE-positive strains, respectively, with notable overlaps of community members. Functional associations of these genes probably confer benefits to these E. coli strains in inhabiting and/or adapting to the bovine intestinal environment and drive their evolution to highly virulent human pathogens under the bovine-adapted genetic background. Our data highlight the importance of large-scale genome sequencing of animal strains in the studies of zoonotic pathogens.

Animals↗
PubMed1984

Intestinal adaptation to cyclic AMP-mediated hypersecretion induced by the heat-labile enterotoxin of Vibrio cholerae and Escherichia coli.

Adaptation to cholera toxin (CT) and the heat-labile enterotoxin (LT) from E. coli is studied in vivo in the rat small intestine. Repeated peroral pretreatment with CT or LT induces protracted inhibition of the intestinal fluid response to these toxins. The CT-induced mucus release from intestinal goblet cells is not influenced by CT pretreatment and the binding of CT to the epithelium remains intact. However, the adenylate cyclase activity, which mediates CT and LT action, is repressed--as judged from the response of this enzyme to both CT, LT and prostaglandin E1. The results suggests that protection against CT and LT acquired in the gut is achieved by desensitization of the adenylate cyclase system.

Adenylyl Cyclases↗
PubMed1990

On the mechanism of action of dexamethasone in a rat mast cell line (RBL-2H3 cells). Evidence for altered coupling of receptors and G-proteins.

Prolonged exposure of rat basophilic leukemia (RBL-2H3) cells, a cultured analog of rat mast cells, to 0.1 microM dexamethasone resulted in global suppression of various stimulatory events in response to Ag and a global enhancement of the same stimulatory events to the adenosine analog, N-(ethylcarboxamide)adenosine (NECA). We had previously shown that Ag and NECA both activate phospholipase C but by different mechanisms; cells that had been treated with cholera or pertussis toxin, for example, responded to Ag but not to NECA with the release of inositol phosphates, increase in levels of cytosolic Ca2+, and secretion. Because the toxins still inhibited the responses to NECA in dexamethasone-treated cells, the effects of dexamethasone may have been exerted at the level of receptor/G-protein coupling rather than at the level of effector systems. Additional evidence for this was the following: 1) NECA-induced hydrolysis of the inositol phospholipids was still enhanced after permeabilizing (with streptolysin O or Staphylococcus alpha-toxin) and washing the cells; 2) the response to the G-protein stimulant, guanosine 5'-(3-O-thio)triphosphate was also enhanced in permeabilized, dexamethasone-treated cells and 3) binding and kinetic studies suggested that the enhanced responsiveness to NECA was attributable in part to an increase in receptor number. The suppressive action of dexamethasone on Ag-induced hydrolysis of inositol phospholipids, however, was readily lost by permeabilizing RBL-2H3 cells. The results indicate, therefore, that treatment with dexamethasone leads to changes in receptor-coupling mechanisms that are either resistant to (i.e., NECA-mediated responses) or reversed by (i.e., Ag-mediated responses) cell permeabilization.

Adenosine↗
PubMed1982

Inhibition of the cyclic AMP-adenylate cyclase system and of secretion by high concentrations of adenosine in the dog thyroid.

Adenosine inhibits cyclic AMP accumulation in stimulated slices and adenylate cyclase in acellular preparations of dog thyroid. The onset of this inhibition is rapid, requires relatively high adenosine concentrations (greater than or equal to 10 microM) and occurs with all activators tested (TSH, PGE1, forskolin and cholera toxin). The manganous ion, which uncouples receptor and cyclase, enhances the inhibition by adenosine. The effect of 2',5'-dideoxyadenosine, the high concentration of adenosine needed, the Mn2- effect and the lack of reversal by methylxanthines all suggest that this effect bears on the "P"-site, i.e. on the cyclase itself. Adenosine also inhibits thyroid secretion, which shows that its effect bears on the follicular cells. However the fact that cyclic AMP and DB cyclic AMP induced secretion are also reduced by adenosine suggests that adenosine also inhibits cyclic AMP action.

Adenosine↗
PubMed2000

Prevalence and characteristics of verotoxin-producing Escherichia coli (VTEC) in stool samples from asymptomatic human carriers working in the meat processing industry in Switzerland.

A total of 5590 stool samples from healthy employees in the meat industry were screened by PCR for verotoxin-producing Escherichia coli (VTEC). The PCR product of VT-encoding genes was detected in 3. 5% of the samples. Phenotypic and genotypic traits of 47 VTEC strains isolated from asymptomatic carriers were characterized. A variety of serotypes was found; one strain belonged to the serotype O157:H7. The majority of the isolates proved to be VT2-positive. Fifty-seven percent of the verotoxin-producing strains harboured the genes for one or several additional virulence associated factors, including intimin (eae, 8.5%), the 60 MDa plasmid (42.5%), enterohaemolysin (EHEC-hlyA, 38.3%), the heat-stable enterotoxin (astA, 6.4%), a serin protease (espP, 6.4%), colicin production (col D157, 12.8%) and a secretion system II (etpD, 10.6%). None of the strains was positive for a specific enzyme with catalase-peroxidase activity (katP).

Bacterial Toxins↗
PubMed2001

Mechanisms of Bordetella pathogenesis.

Bordetella are Gram negative bacteria that cause respiratory tract infections in humans and animals. While at least five different species of Bordetella are known to exist, this review focuses on B. pertussis, B. bronchiseptica and B. parapertussis subspecies. In their virulent phase, all of these bacteria produce a nearly identical set of virulence factors which include adhesins such as filamentous hemagglutinin (FHA), fimbriae and pertactin, as well as toxins such as a bifunctional adenylate cyclase/hemolysin, dermonecrotic toxin, tracheal cytotoxin, a B. pertussis specific pertussis toxin and B. bronchiseptica specific type III secreted proteins. Expression of nearly all of these virulence factors is positively regulated by the products of the bvgAS locus. BvgA and BvgS comprise a two-component signal transduction system that mediates transition between at least three identifiable phases---a virulent (Bvg+) phase, an avirulent (Bvg-) phase and an intermediate (Bvg(i)) phase---in response to specific environmental signals. Bordetella colonize the ciliated respiratory mucosa, a surface designed to eliminate foreign particles, thereby making the adherence and persistence mechanisms of these bacteria crucial. The development of relevant animal models for B. bronchiseptica has enabled us to study Bordetella pathogenesis in the context of natural host-pathogen interactions. In addition, evolutionary studies across the various Bordetella species and detailed analysis of differential regulation of Bvg-activated/repressed genes has greatly enhanced our understanding of the mechanisms of Bordetella pathogenesis.

Animals↗
PubMed2005

Production of a recombinant cholera toxin B subunit-insulin B chain peptide hybrid protein by Brevibacillus choshinensis expression system as a nasal vaccine against autoimmune diabetes.

Mucosally induced tolerance is an attractive strategy for preventing or reducing autoimmune diseases. Here, we produced a recombinant CTB fusion protein linked with autoantigen T cell epitope of insulin B chain peptide 9-23 (C19S) at levels up to 200 mg/L culture media in Brevibacillus choshinensis secretion-expression system. Receptor-competitive assay showed that the CTB-insulin peptide binds to GM1 receptor almost equivalent degree as the native form of CTB. Non-obese diabetes (NOD) mice that spontaneously develop an insulin-dependent diabetes were nasally immunized with CTB-insulin peptide (5 microg) for three times. The nasal treatment significantly reduced the development of insulin-dependent diabetes and peptide specific DTH responses after systemic immunization with the insulin peptide B 9-23(C19S) in CFA. Nasal administration of as high as 50 microg of the peptide alone demonstrated a similar level of the disease inhibition. In contrast, all mice given 5 microg of the insulin peptide alone or 5 microg of insulin peptide with 25 microg of the free form of CTB did not lead to the suppression of diabetes development and DTH responses. Because molecular weight of the insulin peptide is about one tenth of that of the CTB-insulin peptide, the results demonstrate that the recombinant hybrid of autoantigen and CTB increased its tolerogenic potential for nasal administration by up 100-fold on molar base of autoantigen peptide. Taken together, nasally-induced tolerance by administration of the recombinant B. choshinensis-derived hybrid protein of CTB and autoantigen T cell-epitope peptide could be useful mucosal immunetherapy for the control of T cell-mediated autoimmune diseases.

Administration, Intranasal↗
PubMed1996

Transfer of a pertussis toxin expression locus to isogenic bvg-positive and bvg-negative strains of Bordetella bronchiseptica using an in vivo technique.

Bordetella pertussis is the causative agent of whooping cough, a contagious childhood respiratory disease, increasing public concern over the safety of current whole-cell vaccines has led to decreased immunization rates and a subsequent increase in the incidence of the disease. The preparation of safer vaccines is at present concentrated on the production of detoxified virulence factors such as pertussis toxin (PT) for inclusion in acellular vaccine preparations. A permanently avirulent Bordetella bronchiseptica strain was previously engineered to constitutively produce PT. An in vivo cloning technique, based on the principles of conjugal mating and chromosome transfer was employed to transfer the PT expression locus of this strain to virulent and avirulent strains of B. bronchiseptica. This transfer was confirmed by Southern hybridization. An analysis of PT secretion in isogenic virulent and avirulent strains of B. bronchiseptica revealed that the PT produced was cell-associated and not secreted to the growth medium. This evidence suggests that B. bronchiseptica does not possess functional PT secretion (ptl) genes. Therefore, to achieve a PT expression and secretion system suitable for vaccine purposes in Bordetella bronchiseptica, functional ptl genes of B. pertussis are also required.

Bordetella bronchiseptica↗
PubMed1999

Lethal toxin actions and their consequences.

After entry of infectious anthrax spores into the body, host-specific signals induce spore germination, outgrowth of vegetative bacilli and the expression of lethal toxin and other virulence factors. Anthrax lethal toxin (LeTx) is a virulence factor responsible for the major pathologies seen during systemic anthrax infections. Injection of sterile LeTx into test animals mimics the shock and sudden death seen during active bacterial infections. Once large levels of LeTx are produced within the body, destruction of bacteria by administration of antibiotics is usually unsuccessful. The LeTx is believed to be secreted into the bloodstream where it circulates freely throughout the body and binds and enters host cells. Once in the cytoplasm, the lethal factor acts as a zinc-metalloprotease disrupting normal homoeostatic functions. Macrophages are a uniquely sensitive cell type that seem to be vital global mediators of toxin-induced pathologies. Removal of macrophages from mice renders them insensitive to LeTx challenge. Low levels of lethal toxin induce macrophage production, in vitro, of the shock-inducing cytokines TNF and Il-1beta. Higher levels of LeTx cause over-production of reactive oxygen intermediates, bursting of macrophages and release of mediators of shock. We believe that agents capable of blocking key steps of the lethal toxin cascade may prove useful in combating anthrax pathologies.

Animals↗
PubMed1989

Broad-host-range vectors for delivery of TnphoA: use in genetic analysis of secreted virulence determinants of Vibrio cholerae.

Gene fusions between the cholera toxin structural genes and phoA, which encodes bacterial alkaline phosphatase, were identified after TnphoA mutagenesis of the cloned genes in Escherichia coli and were then mobilized into Vibrio cholerae. The activities of the hybrid proteins were detectable in V. cholerae and suggested that, like cholera toxin, they were secreted beyond the cytoplasm. To extend the utility of TnphoA to identify additional genetic export signals in V. cholerae and other gram-negative bacteria, TnphoA delivery vectors utilizing broad-host-range plasmids were developed. By using V. cholerae as a model system, insertion mutants carrying active phoA gene fusions were identified as colonies expressing alkaline phosphatase, which appeared blue on agar containing the indicator 5-bromo-4-chloro-3-indolyl phosphate. Since alkaline phosphatase is active only upon export from the cytoplasm, PhoA+ colonies resulting from the mutagenesis procedure were enriched for insertions in genes that encode secreted proteins. Insertion mutations were identified in the gene encoding a major outer membrane protein, OmpV, and in tcpA, which encodes a pilus (fimbrial) subunit. Mutant strains harboring chromosomal insertions isolated in this manner can be used to assess the role of the corresponding inactivated gene products on survival of V. cholerae in vivo. The expression of the hybrid proteins as determined by measuring alkaline phosphatase activity also allowed the convenient study of virulence gene expression.

Alkaline Phosphatase↗
PubMed2005

The players in a mutualistic symbiosis: insects, bacteria, viruses, and virulence genes.

Aphids maintain mutualistic symbioses involving consortia of coinherited organisms. All possess a primary endosymbiont, Buchnera, which compensates for dietary deficiencies; many also contain secondary symbionts, such as Hamiltonella defensa, which confers defense against natural enemies. Genome sequences of uncultivable secondary symbionts have been refractory to analysis due to the difficulties of isolating adequate DNA samples. By amplifying DNA from hemolymph of infected pea aphids, we obtained a set of genomic sequences of H. defensa and an associated bacteriophage. H. defensa harbors two type III secretion systems, related to those that mediate host cell entry by enteric pathogens. The phage, called APSE-2, is a close relative of the previously sequenced APSE-1 but contains intact homologs of the gene encoding cytolethal distending toxin (cdtB), which interrupts the eukaryotic cell cycle and which is known from a variety of mammalian pathogens. The cdtB homolog is highly expressed, and its genomic position corresponds to that of a homolog of stx (encoding Shiga-toxin) within APSE-1. APSE-2 genomes were consistently abundant in infected pea aphids, and related phages were found in all tested isolates of H. defensa, from numerous insect species. Based on their ubiquity and abundance, these phages appear to be an obligate component of the H. defensa life cycle. We propose that, in these mutualistic symbionts, phage-borne toxin genes provide defense to the aphid host and are a basis for the observed protection against eukaryotic parasites.

Amino Acid Sequence↗
PubMed2003

Expression of Helicobacter pylori vacuolating toxin in Escherichia coli.

VacA is a secreted toxin that plays a role in Helicobacter pylori colonization of the stomach and that contributes to the pathogenesis of peptic ulcer disease. Studies of VacA structure and function have been hindered by the lack of an efficient system for expression and genetic manipulation of this toxin. In this study, we developed methodology for expression of a functionally active VacA toxin in Escherichia coli. We then used a high-throughput screen to analyze a library of mutant toxins with pentapeptide insertions and identified six mutants that lacked the capacity to induce vacuolation of HeLa cells. The capacity to analyze VacA in this heterologous-expression system should greatly facilitate efforts to elucidate the structure and function of this toxin.

Bacterial Proteins↗
PubMed1991

Endothelin increases the synthesis and secretion of atrial natriuretic peptide in neonatal rat cardiocytes.

Endothelin (ET) effected a dose-dependent increment in atrial natriuretic peptide (ANP) secretion and ANP mRNA accumulation in neonatal rat atrial and ventricular cardiocytes but had no effect on the processing of the ANP prohormone to the mature ANP product. The secretagogue effect was not limited by cell density. Both basal and ET-dependent secretory activity were abrogated by the calmodulin antagonist calmidazolium but were unaffected by meclophenamate or pertussis toxin. The magnitude of the ET-dependent increment in ANP secretion was amplified by culturing the cells in a dynamically pulsating (vs. static) environment, implying an interaction between mechanical and agonist-mediated secretory stimuli in this system. ET also promoted immunoreactive ANP release from primary cultures of fetal rat hypothalamic cultures, suggesting that this regulatory function may be generally employed in ANP gene-expressing cells. These findings demonstrate that ET has parallel effects on ANP synthesis and secretion and support a role for this peptide in the regulation of local and circulating levels of the natriuretic hormone.

Animals↗
PubMed2003

Multiple eccrine hidrocystomas: a new therapeutic option with botulinum toxin.

BACKGROUND: Multiple eccrine hidrocystomas are benign cystic lesions that are associated with a chronic course and seasonal variability. Even though in the literature it is presented as a very infrequent pathology, we think this is more a lack of knowledge of the existence of said pathology and the fact that patients confuse it with comedo. OBJECTIVE: To treat multiple eccrine hidrocystomas of the face. RESULTS: We present a case of multiple eccrine hidrocystomas of the face in a cook man. Hidrocystoma is a benign cystic tumor of the sweat glands eccrine or apocrine. Multiple eccrine hidrocystomas are benign cystic lesions that are associated with a chronic course and seasonal variability. They appear like multiple shining small papule. Although a solitary eccrine hidrocystoma can be treated easily with surgical excision, the elimination of multiple lesions is problematic because of their number and location. CONCLUSION: The benefits of BTX-A treatment for multiple eccrine hidrocystomas include ease of application, no risk of scarring, and a good postoperative course. Because of the blockage produced by BTX-A on cholinergic terminals of the parasympathetic system that governs sweat glands secretion, it is suggested that periodic doses of BTX-A are injected in the superficial epidermis in order to treat multiple eccrine hidrocystomas.

Adult↗
PubMed1989

The effect of islet-activating protein (IAP) of pertussis toxin on the spontaneous diabetic syndrome in the rat.

The administration of the Islet-Activating Protein (IAP) of pertussis toxin results in an increased insulin response to oral glucose in a dose- dependent manner. This response can be detected for up to 12 days after a single injection. In addition, IAP increases the number of peripheral blood leucocytes and lymphocytes. Inbred strains of rats differ in the magnitude of the leucocyte but not the insulin responses to IAP. Multiple injections of 1,000 ng of IAP to diabetes-prone BB rats at 50, 64 and 78 days of age caused an increased release in response to glucose challenge and a slight increase in peripheral blood leucocytes when compared to animals receiving saline injections. The prevalence of insulin-dependent diabetes in BB rats was increased in the IAP group as compared to controls. Histolgic examination of the pancreas at the time of detection of diabetes revealed a widespread intense insulitis. We speculate that the increased expression of disease observed in the BB rats receiving IAP may be secondary to the chronic increase in insulin release and/or to an effect on the cells of the immune system.

Animals↗