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PubMed2005

Percolation of the phd repressor-operator interface.

Transcription of the P1 plasmid addiction operon, a prototypical toxin-antitoxin system, is negatively autoregulated by the products of the operon. The Phd repressor-antitoxin protein binds to 8-bp palindromic Phd-binding sites in the promoter region and thereby represses transcription. The toxin, Doc, mediates cooperative interactions between adjacent Phd-binding sites and thereby enhances repression. Here, we describe a homologous operon from Salmonella enterica serovar Typhimurium which has the same pattern of regulation but an altered repressor-operator specificity. This difference in specificity maps to the seventh amino acid of the repressor and to the symmetric first and eighth positions of the corresponding palindromic repressor-binding sites. Thus, the repressor-operator interface has coevolved so as to retain the interaction while altering the specificity. Within an alignment of homologous repressors, the seventh amino acid of the repressor is highly variable, indicating that evolutionary changes in repressor specificity may be common in this protein family. We suggest that the robust properties of the negative feedback loop, the fuzzy recognition in the operator-repressor interface, and the duplication and divergence of the repressor-binding sites have facilitated the speciation of this repressor-operator interface. These three features may allow the repressor-operator system to percolate within a nearly neutral network of single-step mutations without the necessity of invoking simultaneous mutations, low-fitness intermediates, or other improbable or rate-limiting mechanisms.

Amino Acid Sequence↗
PubMed1955

The development of diphtheria vaccines.

Beginning with a discussion of the main types of toxin-antitoxin mixtures of diphtheria vaccine, the author of this article goes on to review briefly the early work done on the conversion of toxin to toxoid and the introduction of adjuvants. Among these, special attention is paid to the aluminium compounds. He also discusses the reasons advanced by different workers for the enhanced activity of vaccine under the influence of adjuvants and the difficulties met with in assessing diphtheria vaccine potency.

Diphtheria↗
PubMed2006

Shutdown decay of mRNA.

Although plasmid-borne and chromosomal toxin-antitoxin (TA) operons have been known for some time, the recent identification of mRNA as the target of at least two different classes of toxins has led to a dramatic renewal of interest in these systems as mediators of stress responses. Members of the MazF/PemK family, the so-called mRNA interferases, are ribonucleases that inhibit translation by destroying cellular mRNAs under stress conditions, while the founder member of the RelE family promotes cleavage of mRNAs through the ribosome. Detailed structures of these enzymes, often in complex with their inhibitors, have provided vital clues to their mechanisms of action. The primary role and regulation of these systems has been the subject of some controversy. One model suggests they play a beneficial role by wiping the slate clean and preventing wasteful energy consumption by the translational apparatus during adaptation to stress conditions, while another favours the idea that their main function is programmed cell death. The two models might not be mutually exclusive if a side-effect of prolonged exposure to toxic RNase activity without de novo synthesis of the inhibitor were a state of dormancy for which we do not yet understand the key to recovery. In this review, I discuss the recent developments in the rapidly expanding field of what I refer to as bacterial shutdown decay.

Adaptation, Biological↗
PubMed1982

Toxin-induced cell membrane injury in guinea pigs given lincomycin.

Guinea pigs treated with lincomycin developed colitis, acute cholecystitis and abnormalities in red blood cell morphology. The present study was designed to study the production of clostridial toxins after lincomycin treatment. Lincomycin produced abnormalities in conventional but not in germ-free guinea pigs. Clostridium difficile was cultured from cecal contents of conventional guinea pigs treated with lincomycin. Cecal filtrate from sick guinea pigs was subjected to Sepharose 4B-CL and Sephadex G-200 column chromatography, yielding a partially purified toxin. Both cecal filtrate and partially purified toxin samples contained a heat labile substance which was cytotoxic to human lung fibroblast Wl-38 cells, and which was neutralized by Clostridium sordelli antitoxin. Toxin samples given orally or intraperitoneally killed normal guinea pigs. Finally, toxin samples induced red cell membrane changes in vitro as well as producing features of acute inflammation in healthy explants of guinea pig cecum and gallbladder in organ culture. Lincomycin treated guinea pigs produced Clostridium difficile toxin(s) which in turn caused diffuse cell membrane injury.

Animals↗
PubMed1976

Large-scale purification and characterization of the exotoxin of Pseudomonas aeruginosa.

The exotoxin (PE) of Pseudomonas aeruginosa was purified from 50-liter cultures by a simple three-step procedure, yielding 135 mg of essentially homogeneous protein. In Ouchterlony gel diffusion, PE produces a single line which does not interact with a diphtheria toxin-antitoxin precipitin line. The protein has a molecular weight of 66,000, an isoelectric point of 5.1, N-terminal arginine, and four disulfide bridges. The amino acid composition shows no apparent similarity to that of diphtheria toxin. The median lethal dose of this PE preparation in mice weighing 20 g is 0.1 mug. The median lethal dose in 350-g rats is 20 mug. The cytotoxicity of PE for mouse L929 fibroblasts is completely neutralized by small amounts of specific pony antitoxin. The exotoxin possesses adenosine diphosphate-ribosylation activity. Both cytotoxic and adenosine diphosphate-ribosylation activities are shown to be properties of the intact 66,000-dalton protein.

Adenosine Diphosphate↗
PubMed1982

The exotoxins of Corynebacterium ulcerans.

The exotoxins produced by ten strains of C. ulcerans (two human, six bovine and two equine) have been studied. On the criteria of toxin-antitoxin neutralisation and immunoprecipitation tests using highly specific diphtheria and C. ovis antitoxins with crude toxic filtrates, (NH4)2SO4 concentrates, and partially purified chromatographic preparations of these, together with the presence or absence of inhibition of the action of staphylococcal beta-haemolysin, and the reaction produced when injected intradermally into rabbits, two toxins could be identified, namely diphtheria toxin and C. ovis toxin. There was no evidence for the production of a third toxin specific for C. ulcerans. Five strains produced both diphtheria and C. ovis toxins. In four diphtheria toxin predominated, but in the fifth C. ovis toxin predominated. Two strains produced only diphtheria toxin and two only C. ovis toxin, though there was good but not complete evidence that a third strain (Revell) also fell into this latter group. Considerable variation occurred in the concentration of each toxin and, where both were present, in the proportion of each.

Animals↗
PubMed2003

A dual lethal system to enhance containment of recombinant micro-organisms.

Active containment systems based on the controlled expression of a lethal gene are designed to increase containment of recombinant micro-organisms used for environmental applications. A major drawback in containment is the existence of mutations that generate surviving cells that cease to respond to the toxic effect of the lethal function. In this work the authors have developed for the first time a strategy to reduce the problem of mutations and increase the efficiency of containment based on the combination of two lethal functions acting on different cellular targets of major concern in containment, DNA and RNA, and whose expression is under control of different regulatory signals. To engineer the dual gene containment circuit, two toxin-antitoxin pairs, i.e. the colicin E3-immunity E3 and the EcoRI restriction-modification systems, were combined. The genes encoding the immunity E3 and the EcoRI methyltransferase proteins (antitoxins) were stably inserted into the chromosome of the host cell, whereas the broad-host-range lethal genes encoding the colicin E3 RNase and the EcoRI restriction endonuclease (toxins) were flanking the contained trait in a plasmid. This dual lethal cassette decreased gene transfer frequencies, through killing of the recipient cells, by eight orders of magnitude, which provides experimental evidence that the anticipated containment level due to the combination of single containment systems is generally achieved. Survivors that escaped killing were analysed and the mutational events involved were characterized.

Bacterial Proteins↗
PubMed1986

Use of implantable intraperitoneal diffusion chambers to study Bordetella pertussis pathogenesis: growth and toxin production in vivo.

A new animal model for Bordetella pertussis infection is described. The system utilizes small chambers bounded by 0.22-micron filter membranes. The chambers are inoculated with B. pertussis, sealed, and surgically implanted into the peritoneal cavity of mice. The chamber system allows dynamic interchange of soluble host and bacterial factors, but not cells. We have used this system to study the growth of various clinical isolates and vaccine strains of B. pertussis, including an isogenic virulent/avirulent pair. All virulent strains tested grew well and had remarkably similar growth kinetics. We monitored cellular and humoral host responses, including the response to pertussis toxin. Antitoxin appeared 21-37 days after implantation of the chambers. The model allows us to dissociate the ability of an organism to grow in vivo from other properties (e.g., attachment and toxin production) that may be involved in pathogenesis.

Animals↗
PubMed2005

Botulinum toxin.

Botulinum toxin is regarded as the most lethal substance known. It is estimated that the human LD50 for inhalation botulism is 1 to 3 nanograms of toxin/kilogram body mass. Although only three cases of inhalational botulism have been described, an understanding of the pathophysiology of food-borne outbreaks, wound botulism, and infant botulism, and their therapies, enables the medical community to plan treatment in the event of an aerosol release of botulinum toxin. Antitoxin, vaccine, and F(ab')2 immune fragment therapies are discussed as adjuncts to supportive therapy.

Bioterrorism↗
PubMed1990

Long term serologic follow-up after pertussis immunization.

Neutralizing antibodies to pertussis toxin (antitoxin) were determined in 201 blood samples from 4-year-old children. They had received primary immunization at 6 to 8 months of age with an acellular (n = 149) or a whole cell (n = 52) pertussis vaccine and 195 of them had received a booster dose of the acellular vaccine 9 to 16 months later. Data on exposure to pertussis and occurrence of pertussis were also collected. There was a rapid decrease of antitoxin between immediate postbooster titers and those measured 24 months later. This decrease per month was significantly greater than that after the primary immunization series (P less than 0.001). Neither the number nor the spacing of acellular vaccine doses given for primary series influenced the titers found 24 months after the booster. An antitoxin response was still measurable in 86% of the 196 four-year-old children. None of 19 exposed children developed whooping cough, which suggested that the antibody concentrations during the follow-up period were sufficient for protection. The results indicate a need for long term follow-up studies in the evaluation of new vaccines and immunization schedules.

Antibodies, Bacterial↗
PubMed2006

Dynamic metabolic adjustments and genome plasticity are implicated in the heat shock response of the extremely thermoacidophilic archaeon Sulfolobus solfataricus.

Approximately one-third of the open reading frames encoded in the Sulfolobus solfataricus genome were differentially expressed within 5 min following an 80 to 90 degrees C temperature shift at pH 4.0. This included many toxin-antitoxin loci and insertion elements, implicating a connection between genome plasticity and metabolic regulation in the early stages of stress response.

Antitoxins↗
PubMed2002

Bacterial toxin RelE induces apoptosis in human cells.

The bacterial protein RelE severely restricts prokaryotic cell growth, probably by acting as a global inhibitor of translation. It is ubiquitous in prokaryotes as part of the RelE-RelB toxin-antitoxin system, and may be activated by nutritional stress. When the relE gene from Escherichia coli was expressed inducibly in a human osteosarcoma cell line, it was shown to retard growth and to lead to cell death by apoptosis. RelE is therefore unusual among bacterial toxins in possessing broad activity against both prokaryotes and eukaryotes, perhaps by acting on evolutionarily conserved components of the translation machinery.

Anti-Bacterial Agents↗
PubMed2006

Ectopic overexpression of wild-type and mutant hipA genes in Escherichia coli: effects on macromolecular synthesis and persister formation.

Persistence is an epigenetic trait that allows a small fraction of bacteria, approximately one in a million, to survive prolonged exposure to antibiotics. In Escherichia coli an increased frequency of persisters, called "high persistence," is conferred by mutations in the hipA gene, which encodes the toxin entity of the toxin-antitoxin module hipBA. The high-persistence allele hipA7 was originally identified because of its ability to confer high persistence, but little is known about the physiological role of the wild-type hipA gene. We report here that the expression of wild-type hipA in excess of hipB inhibits protein, RNA, and DNA synthesis in vivo. However, unlike the RelE and MazF toxins, HipA had no effect on protein synthesis in an in vitro translation system. Moreover, the expression of wild-type hipA conferred a transient dormant state (persistence) to a sizable fraction of cells, whereas the rest of the cells remained in a prolonged dormant state that, under appropriate conditions, could be fully reversed by expression of the cognate antitoxin gene hipB. In contrast, expression of the mutant hipA7 gene in excess of hipB did not markedly inhibit protein synthesis as did wild-type hipA and yet still conferred persistence to ca. 10% of cells. We propose that wild-type HipA, upon release from HipB, is able to inhibit macromolecular synthesis and induces a bacteriostatic state that can be reversed by expression of the hipB gene. However, the ability of the wild-type hipA gene to generate a high frequency of persisters, equal to that conferred by the hipA7 allele, may be distinct from the ability to block macromolecular synthesis.

Arabinose↗
PubMed2002

Molecular characterization of long direct repeat (LDR) sequences expressing a stable mRNA encoding for a 35-amino-acid cell-killing peptide and a cis-encoded small antisense RNA in Escherichia coli.

Genome sequence analyses of Escherichia coli K-12 revealed four copies of long repetitive elements. These sequences are designated as long direct repeat (LDR) sequences. Three of the repeats (LDR-A, -B, -C), each approximately 500 bp in length, are located as tandem repeats at 27.4 min on the genetic map. Another copy (LDR-D), 450 bp in length and nearly identical to LDR-A, -B and -C, is located at 79.7 min, a position that is directly opposite the position of LDR-A, -B and -C. In this study, we demonstrate that LDR-D encodes a 35-amino-acid peptide, LdrD, the overexpression of which causes rapid cell killing and nucleoid condensation of the host cell. Northern blot and primer extension analysis showed constitutive transcription of a stable mRNA (approximately 370 nucleotides) encoding LdrD and an unstable cis-encoded antisense RNA (approximately 60 nucleotides), which functions as a trans-acting regulator of ldrD translation. We propose that LDR encodes a toxin-antitoxin module. LDR-homologous sequences are not pre-sent on any known plasmids but are conserved in Salmonella and other enterobacterial species.

Amino Acid Sequence↗
PubMed2003

The YefM antitoxin defines a family of natively unfolded proteins: implications as a novel antibacterial target.

Although natively unfolded proteins are being observed increasingly, their physiological role is not well understood. Here, we demonstrate that the Escherichia coli YefM protein is a natively unfolded antitoxin, lacking secondary structure even at low temperature or in the presence of a stabilizing agent. This conformation of the protein is suggested to have a key role in its physiological regulatory activity. Because of the unfolded state of the protein, a linear determinant rather than a conformational one is presumably being recognized by its toxin partner, YoeB. A peptide array technology allowed the identification and validation of such a determinant. This recognition element may provide a novel antibacterial target. Indeed, a pair-constrained bioinformatic analysis facilitated the definite determination of novel YefM-YoeB toxin-antitoxin systems in a large number of bacteria including major pathogens such as Staphylococcus aureus, Streptococcus pneumoniae, and Mycobacterium tuberculosis. Taken together, the YefM protein defines a new family of natively unfolded proteins. The existence of a large and conserved group of proteins with a clear physiologically relevant unfolded state serves as a paradigm to understand the structural basis of this state.

Amino Acid Sequence↗
PubMed1999

A ten year follow-up after immunization with a two component acellular pertussis vaccine.

OBJECTIVES: To investigate the duration of antitoxin response and immunity to pertussis 10 years after priming with either two or three doses of a two component acellular pertussis vaccine or with three doses of a whole cell vaccine and then boostered with the acellular vaccine. SUBJECTS: At 11 years of age 207 of 304 (68%) children of the original cohort returned for a blood sample and 262 (86%) participated by answering a questionnaire. METHODS: Neutralizing antibodies to pertussis toxin (antitoxin) were analyzed by the Chinese hamster ovary cell assay. Clinical pertussis and pertussis exposure were investigated by a structured questionnaire. RESULTS: Measurable antitoxin was found in 77% of the samples, with no differences by type of vaccine or by the number of doses given for priming. A significant decrease of antibody concentration (P<0.001) was noted from the previous recall at 4 years of age, and significant titer rises were found for 14% of the children, irrespective of known exposure. Confirmed pertussis during follow-up, as defined in the study, was reported for 14 of 262 (5%) children. CONCLUSIONS: The study showed that antitoxin concentrations are maintained in a situation of endemic pertussis and indicated that the long term protection after an acellular booster was good, irrespective of type of vaccine or the number of doses of acellular vaccine given for priming.

Antibodies, Bacterial↗