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PubMed2004

Insights into the specificity of RNA cleavage by the Escherichia coli MazF toxin.

The mazEF (chpA) toxin-antitoxin system of Escherichia coli is involved in the cell response to nutritional and antibiotic stresses as well as in bacterial-programmed cell death. Valuable information on the MazF toxin was derived from the determination of the crystal structure of the MazE/MazF complex and from in vivo data, suggesting that MazF promoted ribosome-dependent cleavage of messenger RNA. However, it was concluded from recent in vitro analyses using a MazF-(His6) fusion protein that MazF was an endoribonuclease that cleaved messenger RNA specifically at 5'-ACA-3' sites situated in single-stranded regions. In contrast, our work reported here shows that native MazF protein cleaves RNA at the 5' side of residue A in 5'-NAC-3' sequences (where N is preferentially U or A). MazF-dependent cleavage occurred at target sequences situated either in single- or double-stranded RNA regions. These activities were neutralized by a His6-MazE antitoxin. Although essentially consistent with previous in vivo reports on the substrate specificity of MazF, our results strongly suggest that the endoribonuclease activity of MazF may be modulated by additional factors to cleave messenger and other cellular RNAs.

Animals↗
PubMed1978

Neutralization of Clostridium difficile toxin by Clostridium sordellii antitoxins.

Neutralization of Clostridium difficile toxin by Clostridium sordellii antitoxin was studied by cytotoxicity assay in tissue culture. The sources of toxin were stools from two patients with pseudomembranous colitis and a culture filtrate of C. difficile isolated from one of the patients. C. sordellii antitoxin was available either in monovalent form or as gas gangrene polyvalent antitoxin. The potency of antitoxins against C. difficile determined by cytotoxicity assay did not correlate with the established values reported for mouse protection tests against C. sordellii toxin. An equivalent zone of optimal neutralization was demonstrated for stool toxin, and a slightly different one for culture toxin. The rate of neutralization appeared to be instantaneous, either at 24 or at 37 degrees C. The efficacy of antitoxin in preventing cytotoxicity in cultured cells preexposed to toxin decreased rapidly with preexposure time. The union between toxin and antitoxin could be readily dissociated by simple dilution or by ammonium sulfate precipitation followed by dissociated by simple dilution or by ammonium sulfate precipitation followed by dilution. Continued incubation of toxin-antitoxin mixture did not increase the firmness of the union; on the contrary, more dissociation occurred. The unusual looseness of the toxin-antitoxin union is probably relatd to lack of serological specificity or affinity. Based on these observations, a practical diagnostic method for antibiotic-induced colitis is outlined.

Antitoxins↗
PubMedDate not supplied

[Toxoids of botulinum toxin type G].

Clostridium botulinum type G toxin was obtained by the dialysis sac culture method. Crude toxin was submitted to precipitation either by 4.5 M (NH4)2SO4 (Table 2) or ethanol 96% up to 25% final concentration (Table 3). Aliquots of crude toxin and fractions from the precipitation methods were activated by trypsin, detoxificated by formalin and adsorbed with aluminum phosphate. Twelve preparations of toxoids (Table 1) were obtained and assayed in laboratory animals. The immune response was studied through the toxin-antitoxin neutralization test, set up at a level of 4,000 mouse LD50 per ml. Guinea pigs had the highest titer of antitoxin (64,000 anti-mouse-LD50/ml) after its immunization with toxoid prepared with toxin precipitated by 4.5 M ammonium sulphate activated by trypsin and adsorbed with aluminum phosphate. Rabbits responded with a lower titer of antitoxin but had a similar response than guinea pigs to the same toxoids (Table 5). Chickens did not show any antitoxin response above 4,000 anti-mouse-LD50 per ml.

Animals↗
PubMed2006

Fluoroquinolone resistance and plasmid addiction systems: self-imposed selection pressure?

Multi-antibiotic-resistant Gram-negative pathogens are becoming more prevalent and an association exists between chromosomally conferred fluoroquinolone resistance and the presence of plasmid-borne resistances, such as extended spectrum beta-lactamases. This link is not wholly explained by strain spread or the presence of fluoroquinolone-modifying enzymes. Plasmid-encoded toxin-antitoxin addiction systems enforce plasmid maintenance in bacteria and, like fluoroquinolones, some toxins target DNA gyrase. Bacteria can develop resistance to these toxins, which would free the cell of the plasmid addiction and allow it to ditch the "excess baggage". We hypothesize that these plasmid-encoded gyrase toxins might contribute to, or predispose towards, clinically significant fluoroquinolone resistance, and that the plasmid-encoded quinolone resistance determinant, Qnr, may facilitate this. Establishing the extent and mechanisms of cross-resistance to toxins and fluoroquinolones will aid the management of resistance and may contribute to the development of novel antimicrobials.

Anti-Bacterial Agents↗
PubMed2006

Two higBA loci in the Vibrio cholerae superintegron encode mRNA cleaving enzymes and can stabilize plasmids.

Vibrio cholerae codes for 13 toxin-antitoxin (TA) loci all located within the superintegron on chromosome II. We show here that the two higBA TA loci of V. cholerae encode functional toxins, HigB-1 and HigB-2, whose ectopic expression inhibits cell growth of Escherichia coli, and functional antitoxins, HigA-1 and HigA-2, which counteract the toxicity of the cognate toxins. Three hours of ectopic expression of the HigB toxins resulted in bacteriostasis without any detectable loss of cell viability. The HigB toxins inhibited translation by cleavage of mRNA. Efficient mRNA cleavage occurred preferentially within the translated part of a model mRNA and only when the mRNA was translatable. Promoter analysis in V. cholerae and E. coli showed that the two higBA loci are both transcribed into bi-cistronic mRNAs and that the higBA-2 mRNA is leaderless. Transcription of the two higBA loci was strongly induced by amino acid (aa) starvation in V. cholerae and E. coli, indicating that the regulatory mechanisms of transcriptional induction are conserved across the two species. Both higBA loci stabilized a test-plasmid very efficiently in E. coli, raising the possibility that the loci contribute to maintain genetic stability of the V. cholerae superintegron. Based on these results we discuss the possible biological functions of the TA loci of V. cholerae.

Arabinose↗
PubMed1987

Shiga-like toxin production and attaching effacing activity of Escherichia coli associated with calf diarrhea.

Four hundred twenty-nine isolates of Escherichia coli from calves were tested for the production of HeLa cell cytotoxin(s). Isolates that produced enough cytotoxin to be detected in culture supernatants of iron-depleted broth were considered to produce increased amounts of cytotoxins. Isolates also were tested for homology with a DNA probe for a gene that encodes localized adherence of human enteropathogenic E coli. Four isolates produced increased amounts of cytotoxin that was neutralized by Shiga antitoxin (toxin designated as Shiga-like toxin-I [SLT-I]). A 5th isolate produced increased amounts of cytotoxin (SLT+) that was not neutralized by the Shiga antitoxin, but was neutralized by antitoxin against a variant of SLT (toxin designated as SLT-II). None of the isolates hybridized with the probe for the localized adherence gene. Three of the SLT+ isolates belonged to human enteropathogenic E coli serogroups O26 and O111. All 5 of the SLT+ isolates were from calves with diarrhea, but none of the 5 SLT+ isolates contained genes for classic heat-labile or heat-stable enterotoxins, for K99 fimbriae, or for invasiveness; neither did any of them adhere to HeLa cells in culture. Three of the 5 SLT+ isolates had attaching and effacing activities when inoculated into ligated intestinal loops of rabbits. One of the isolates with attaching and effacing activity in rabbits was originally isolated from a calf with lesions characteristic of those produced by attaching effacing E coli (AEEC). Calves inoculated with this SLT+ AEEC isolate developed focal colonic lesions characteristic of those produced by AEEC, but did not develop diarrhea.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1976

Serological classification and typing of Clostridium botulinum.

Serological classification of Cl. botulinum, based on the antigenic structure of the toxins produced, is distinguished by the behaviour of the toxin-antitoxin mixtures in in vivo neutralization tests. Observations on the dissimilarity between strains within types, the behaviour of antitoxins in the cross-neutralization tests, the established concepts of the antigenic structure of the toxin types and the lack of a standard methodology for typing, have led to the definition of the terms efficiency, type, subtype, intratypic serological variant (ISV), and degree of serological homology. These definitions are primarily applied to typing and to the establishment of the taxonomic serological categories of type, subtype and ISV. In the case of antitoxin standardization, the accepted standard methods must be followed.

Clostridium botulinum↗
PubMed2005

Development without germ cells: the role of the germ line in zebrafish sex differentiation.

The progenitors of the gametes, the primordial germ cells (PGCs) are typically specified early in the development in positions, which are distinct from the gonad. These cells then migrate toward the gonad where they differentiate into sperms and eggs. Here, we study the role of the germ cells in somatic development and particularly the role of the germ line in the sex differentiation in zebrafish. To this end, we ablated the germ cells using two independent methods and followed the development of the experimental fish. First, PGCs were ablated by knocking down the function of dead end, a gene important for the survival of this lineage. Second, a method to eliminate the PGCs using the toxin-antitoxin components of the parD bacterial genetic system was used. Specifically, we expressed a bacterial toxin Kid preferentially in the PGCs and at the same time protected somatic cells by uniformly expressing the specific antidote Kis. Our results demonstrate an unexpected role for the germ line in promoting female development because PGC-ablated fish invariably developed as males.

Animals↗
PubMed1989

Sixteen-month follow-up of antibodies to pertussis toxin after primary immunization with acellular or whole cell vaccine.

Antibodies to pertussis toxin (antitoxin) were measured in three blood samples drawn during a 16- to 17-month follow-up of infants immunized with adsorbed two component acellular pertussis vaccine (JNIH-6) or plain whole cell vaccine. A significant decrease of antitoxin concentration was noted between each follow-up in the acellular vaccine groups (P less than 0.005). The higher antitoxin titers induced by three doses or by two doses spaced by 2 months compared with two doses with 1-month interval disappeared with time. The antitoxin titers among high responders to three doses of whole cell vaccine paralleled those of the acellular vaccinees but at a significantly lower level. Reported exposure to pertussis did not significantly alter the decrease of antitoxin titers. The study also showed that acellular pertussis vaccine induced an antitoxin response still measurable in greater than or equal to 97 and greater than or equal to 91% of samples drawn 10 to 11 and 16 to 17 months after primary immunization, respectively.

Antitoxins↗
PubMed2006

Increased persistence in Escherichia coli caused by controlled expression of toxins or other unrelated proteins.

Bacterial populations contain persisters, cells which survive exposure to bactericidal antibiotics and other lethal factors. Persisters do not have a genetic resistance mechanism, and their means to tolerate killing remain unknown. In exponentially growing populations of Escherichia coli the frequency of persister formation usually is 10(-7) to 10(-5). It has been shown that cells overexpressing either of the toxic proteins HipA and RelE, both members of the bacterial toxin-antitoxin (TA) modules, have the ability to form more persisters, suggesting a specific role for these toxins in the mechanism of persistence. However, here we show that cells expressing proteins that are unrelated to TA modules but which become toxic when ectopically expressed, chaperone DnaJ and protein PmrC of Salmonella enterica, also form 100- to 1,000-fold more persisters. Thus, persistence is linked not only to toxicity caused by expression of HipA or dedicated toxins but also to expression of other unrelated proteins.

Bacterial Proteins↗
PubMed1984

Direct visualization of redistribution and capping of fluorescent gangliosides on lymphocytes.

Fluorescent derivatives of gangliosides were prepared by oxidizing the sialyl residues to aldehydes and reacting them with fluorescent hydrazides. When rhodaminyl gangliosides were incubated with lymphocytes, the cells incorporated them in a time- and temperature-dependent manner. Initially, the gangliosides were evenly distributed on the cell surface but were redistributed into patches and caps by antirhodamine antibodies. When the cells were then stained with a second antibody or protein A labeled with fluorescein, the fluorescein stain revealed the coincident movement of both the gangliosides and the antirhodamine antibodies. When the cells were treated with both rhodamine and Lucifer yellow CH-labeled gangliosides, the antirhodamine antibodies induced patching and capping of both fluorescent gangliosides but had no effect on cells incubated only with Lucifer yellow CH-labeled gangliosides. In addition, capping was observed on cells exposed to cholera toxin, antitoxin antibodies, and rhodamine-labeled protein A, indirectly showing the redistribution of endogenous ganglioside GM1, the cholera toxin receptor. By incorporating Lucifer yellow CH-labeled GM1 into the cells and inducing capping as above, we were able to demonstrate directly the coordinate redistribution of the fluorescent GM1 and the toxin. When the lymphocytes were stained first with Lucifer yellow CH-labeled exogenous ganglioside GM3, which is not a toxin receptor, there was co-capping of endogenous GM1 (rhodamine) and exogenous GM3 (Lucifer yellow CH). These results suggest that gangliosides may self-associate in the plasma membrane which may explain the basis for ganglioside redistribution and capping.

Animals↗
PubMed1979

Use of ganglioside affinity filters to identify toxigenic strains of Clostridium botulinum types C and D.

Clostridium botulinum neurotoxin is synthesized by toxic clones grown anaerobically on ganglioside affinity filters. The toxin binds to the filters and is detected by reaction with 125I-immunoglobulin G from type-specific antitoxin. Toxin spots from culture filtrates were similarly identified. The C. botulinum type C and D strains were selected for developing this affinity filter assay because synthesis of the C1 and D toxins is bacteriophage dependent. Toxigenic clones were distinguished from prophage-cured atoxigenic derivatives. These studies represent a first step toward the development of a general nonbiological screening procedure for identifying botulinal toxin and toxigenic cells. The affinity filter methodology should facilitate genetic analysis of the basis of C. botulinum toxicity.

Bacteriological Techniques↗