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PubMed2004

Diphtheria immunity status in Egypt.

The aim of this study was to determine immune status to corynebacterium diphtheria by screening for protective antibodies in a sample of Egyptian population. The study population consisted of 709 healthy subjects aged from 2 months to 105 years, inhabitants of 6 regions of Egypt. The study utilized Enzyme linked immunosorbent assay (ELISA) to measure serum levels IgG antibodies reactive with diphtheria toxoid. Levels of diphtheria toxoid antibody > or = 0.1 IU/ ml were defined as immune/protected, 23.9 % of the population were found to be susceptible to diphtheria (IgG level < 0.01 IU/ml), 43% had basic protection (0.01-0.09 IU/ml), and 33.1% were fully protected (0.1 IU/ml). The results revealed that serum levels of antitoxin antibodies decreased in old ages (< 60 y) with the females being more susceptible then males. These results recommend a booster immunization for the susceptible age groups.

Adolescent↗

PubMed1977

Artificial hybrid protein containing a toxic protein fragment and a cell membrane receptor-binding moiety in a disulfide conjugate. II. Biochemical and biologic properties of diphtheria toxin fragment A-S-S-human placental lactogen.

The biochemical and biologic properties of a purified disulfide conjugate of diphtheria toxin fragment A and human placental lactogen (toxin A-hPL) have been studied by (a) assaying the ADP-ribosyltransferase activity of the intact conjugate, (b) assaying the binding of the intact conjugate to mammary gland plasma membrane lactogenic receptors, and (c) assaying the effect of the conjugate on the rate of protein synthesis in rabbit mammary gland explants maintained in organ culture. The toxin A-hPL conjugate retains one-third of the NAD+:EF-2 ADP-ribosyltransferase activity of toxin A, and 26% of the hPL-binding activity to lactogenic receptors. Binding activity was demonstrated by radioreceptor assay and by assaying toxin A activity bound to membranes which was competitively displaced by excess hPL. Since the toxin A-hPL conjugate retained activities of its separate subunits, it could be regarded as a structural analogue of nicked diphtheria toxin with replacement of the original membrane-binding chain by another binding chain that is specific for lactogenic receptor. However, the conjugate failed to inhibit protein synthesis in organ-cultured mammary gland explants, although these were sensitive to native diphtheria toxin and could bind hPL. It is concluded from these results that the toxin A-hPL conjugate does not act as a functional analogue of diphtheria toxin with altered receptor specificity, and that the hPL receptor cannot mediate the entry of toxin A or toxin A-hPL from membrane-bound conjugate into the cytosol site of action of toxin A.

Adenosine Diphosphate Sugars↗

PubMed1991

[The characteristics of Corynebacterium diphtheriae adhesins].

The study of the properties of C. diphtheriae adhesins revealed the absence of their thermostability, which suggested the protein nature of these adhesins. C. diphtheriae also showed pronounced mannose-resistant hemagglutinating activity, as this activity remained unchanged even in the presence of d-mannose. The comparison of the adhesive activity of C. diphtheriae with their phage and corycine sensitivity revealed essential differences between these macroorganisms in the degree of their adhesiveness. The phage lysability and corycine sensitivity of C. diphtheriae strains, determined by the properties of their surface structure, correlated with the degree of their activity.

Bacterial Adhesion↗

PubMed1991

[Clinical aspects of diphtheria in infants].

The symptomatology of different forms of diphtheria was analyzed in 49 patients under 3 year of age. It has been established that in infants, diphtheria is marked by the diversity of localizations and a fairly high portion of associated toxic diphtheria of the stomatopharynx and disseminated croup. These gravest forms are fairly difficult to recognize them clinically. Their early diagnosis should rest on the presence of the pronounced signs of intoxication, edema of the lonsils and stomatopharyngeal mucosa, and pannicular patches spreading beyond the tonsils. In the presence of toxic diphtheria, the stages of croup become shorter while the recognition of its symptoms is embarrassing.

Child, Preschool↗

PubMed1990

[Classical pseudomembranous diphtheria caused by Corynebacterium ulcerans].

In a 63-year-old patient presenting with signs of classical diphtheria including membranous pharyngotracheobronchitis and myocarditis, Corynebacterium ulcerans was isolated in pure culture from the membranes. The strain produced a toxin specific for C. ulcerans but no diphtheria toxin. The patient was discharged after a complicated hospital course including respiratory and cardiac failure. Besides Corynebacterium diphtheriae, which has very rarely been isolated in Switzerland in recent years, Corynebacterium ulcerans should be considered as a cause of classical diphtheria.

Bacterial Toxins↗

PubMed1989

Enhancement of immunotoxin efficacy by acid-cleavable cross-linking agents utilizing diphtheria toxin and toxin mutants.

We have utilized a new class of acid-cleavable protein cross-linking reagents in the construction of antibody-diphtheria toxin conjugates (Srinivaschar, K., and Neville, D. M., Jr. (1989) Biochemistry 28, 2501-2509). The potency of anti-CD5 conjugates assayed by inhibition of protein synthesis on CD5 bearing cells (Jurkat) is correlated with cross-linker hydrolytic rates. The maximum increase in potency of the cleavable conjugates over non-cleavable conventional conjugates is 50-fold and is specific for the CD5 uptake route as judged by competition with excess anti-CD5. The potency of conjugates made from diphtheria toxin and the anti-high molecular weight melanoma-associated antigen (HMW-MAA) is enhanced 3-10-fold by a cleavable cross-linker. However the potency of transferrin or anti-CD3 diphtheria toxin conjugates is only minimally enhanced (2-3-fold). Mutant diphtheria toxins, CRM103 and CRM9, previously shown to express less than 1/100 of the wild type in binding affinity were substituted into these conjugates as probes for possible intracellular toxin receptor interactions. Both mutants were equally as toxic to Jurkat target cells exhibiting 1/700 the wild-type potency. CRM9 non-cleavable conjugates were equally as potent as wild-type conjugates for transferrin and anti-CD3-mediated uptake but not for anti-CD5-mediated uptake where toxicity was reduced 60-fold over the wild-type analog. The cleavable cross-linker enhanced the toxicity of anti-CD5-CRM103 and anti-CD5-CRM9 conjugates, but potency was only 1/10 that of the analogous wild-type cleavable conjugate. These data are consistent with a model in which potentiation of toxicity of the anti-CD5 and anti-high molecular weight melanoma-associated antigen conjugates by the cleavable cross-linker occurs from an enhanced intracellular toxin-toxin receptor interaction that ultimately results in increased toxin translocation to the cytosol compartment. In contrast, these data indicate that the anti-CD3 and transferrin uptake systems do not require this interaction in agreement with previous work (Johnson, V.G., Wilson, D., Greenfield, L., and Youle, R. J. (1988) J. Biol. Chem. 263, 1295-1300).

Animals↗

PubMed1989

[Detection of toxin and evaluation of the degree of toxin-formation of Corynebacterium diphtheriae using immunoenzyme analysis].

Toxin production and the intensity of toxin formation in 265 C. diphtheriae strains circulating in different areas of the USSR have been studied by the method of the enzyme-linked immunosorbent assay (ELISA). This study has been carried out with the use of the assay system consisting of monoclonal antibodies to the COOH-area of the B-fragment of the toxin molecule adsorbed onto the surface of polystyrene plates, affinity-purified polyclonal antidiphtheria antibodies labeled with horse-radish peroxidase and substrate indicator mixture (5-aminosalicylic acid and hydrogen peroxide). Some specific features of using ELISA for the detection of C. diphtheriae toxin directly in liquid culture medium are presented. High sensitivity, specificity and good reproducibility of this method permitting the detection of C. diphtheriae toxin and the determination of the intensity of toxin formation in the C. diphtheriae strains under study are shown. The method may be recommended for practical use at health institutions.

Antibodies, Monoclonal↗

PubMed1989

[A report of an outbreak of diphtheria in Anshan area].

This paper reports an outbreak of diphtheria and the result of appropriate preventive and therapeutic measures in Anshan area from Dec. 1984 to Dec. 1987. This epidemic of diphtheria occurred mainly in a camp of reform though labour organization and in a spring sanatorium among a population of young adult people with higher level of antibodies. It was proved that the special infection origin was a strain of nontoxic diphtheria bacilli. After a combined management including of injection of a refined diphtheria toxoid and an environment disinfection, the incidence of the disease dropped markedly.

Adolescent↗

PubMed1987

Genetic assembly and selective toxicity of diphtheria-toxin-related polypeptide hormone fusion proteins.

The reports of Miyanohara et al. (1986) and Murphy et al. (1986) were the first to describe the genetic construction, expression, and receptor-specific selective toxicity of a chimaeric toxin. In the present report, we have extended these earlier observations and have shown that the fusion of a modified gene encoding IL-2 to a truncated diphtheria toxin gene also results in the expression of a biologically active chimaeric IL-2 toxin. In both instances we have used receptor-binding-domain substitution and have genetically coupled those portions of the diphtheria toxin structural gene that encode the ADP-ribosyl transferase activity of fragment A and lipid-associating domains of fragment B to modified genes which encode either the polypeptide hormone alpha-MSH or the T-cell growth factor IL-2. The chimaeric toxins expressed from these gene fusions have been shown to be selectively targeted to those eukaryotic cells that carry specific surface receptors for the ligand compounds of the hybrid. For example, in the case of the IL-2 toxin, it is clear that the selective action of this hybrid protein is based upon both its diphtheria-toxin and IL-2-related components. Following binding to the IL-2R on activated and/or malignant T-cell, IL-2 toxin is internalized by receptor-mediated endocytosis. Upon acidification of the endosome, diphtheria toxin fragment B portions of the chimaeric toxin facilitate the delivery of fragment A to the cytosol where it catalyses the ADP ribosylation of EF-2. The assembly of chimaeric toxins at the level of the gene offers several advantages over chemical linkage. Since chemical linkage of the toxophore and ligand components of the conjugate toxins requires activation of the epsilon-amino moiety of lysine residues with reagents that will allow for subsequent disulphide linkage, the precise site of coupling is generally not known. In addition, there has been considerable concern over the lability of the disulphide bond between the toxophore and ligand components in vivo due to the action of disulphide reductases. The assembly of chimaeric toxins at the level of the gene allows for precise linkage of the toxophore and ligand components. Since the linkage between the toxophore and ligand is a peptide bond, the chimaeric toxin should be stable in vivo. In addition, the genetic construction of chimaeric toxins also allows for further protein engineering through site-directed mutagenesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

PubMed1988

Specific chemical cleavage of diphtheria toxin with hydroxylamine. Purification and characterization of the modified proteins.

Specific chemical cleavage of diphtheria toxin with hydroxylamine was performed to remove peptides of 10 and 7 kDa from the carboxyl terminus. The resulting modified proteins of 51 and 48 kDa (HA51DT and HA48DT, respectively) were purified and characterized with respect to structural and biological properties. The 51-kDa toxin binds to ATP-agarose, as does intact diphtheria toxin, while HA48DT does not bind to the nucleotide matrix. Neither modified toxin binds to the membranes of diptheria toxin-sensitive cells, and, consequently, neither is toxic. However, when covalently linked to a membrane binding moiety, both HA51DT and HA48DT are toxic. Cell-killing ability during a short exposure time indicated that concanavalin A (Con A) derivatives of diphtheria toxin and HA51DT are equally toxic, ConA HA48DT being somewhat less toxic, while the conjugate of ConA to A-chain kills a small number of cells only at inordinately high concentration (1 microM). We have thus separated the cell membrane binding function of diphtheria toxin from its membrane permeation function by removing specific small peptides from the carboxyl terminus. These modified toxins may have applications in the preparation of highly potent hybrid toxins.

Cell Line↗

PubMed1988

The 1985 national immunisation survey: diphtheria, tetanus, and pertussis (whooping cough)

In April 1985 a national immunisation survey was conducted in which sera were collected from almost 3000 randomly selected children throughout New Zealand. The sera collected were from about 1000 new school entrants (mean age 5 years), 1000 standard 3 students (mean age 10 years), and 1000 form 4 students (mean age 15 years). The sera were tested for diphtheria and tetanus immunity and antibody to pertussis by enzyme-linked immunosorbent assay (ELISA) tests. The percentage of those immune to diphtheria decreased with age from 73.1% in the 5 year olds to 53.7% in the 15 year olds. The percentage of those immune to tetanus decreased with age from 66.9% in the 5 year olds to 54.6% in the 10 year olds but then increased to 64.0% in the 15 year olds. While more than 71.0% of the 10 and 15 year olds had measurable antibody to pertussis, only a low 54.4% of the 5 year olds did. The proportion immune to diphtheria and tetanus in both Maoris and Europeans was approximately similar in all three age groups. More Maoris (78.9%) than Europeans (66.1%) had antibody to pertussis. When the data had been standardised for age and ethnic group the percentage with antibody to pertussis and immunity to diphtheria was highest in the southern region, while for tetanus immunity the percentage immune was highest in the northern and southern regions. We conclude that a sizeable pool of new school entrants (mean age 5 years) without antibody to pertussis is accumulating at a time when pertussis still persists.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1988

The pH-dependent conformational change of diphtheria toxin.

Labeling by a hydrophobic photoactivatable reagent and limited proteolysis have been used to study conformational changes of diphtheria toxin related to its pH-dependent membrane insertion and translocation. TID (3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine) labels diphtheria toxin at pH 5 much more efficiently than at pH 7, both in the presence and absence of lipid vesicles. In the absence of membranes, the extent of labeling is greater and the pH dependence is stronger. As analyzed on sodium dodecyl sulfate-polyacrylamide gels and by high pressure liquid chromatography, both the A- and B-subunits and most of the cyanogen bromide fragments of the toxin are labeled by TID at acid pH. The products of trypsin cleavage of diphtheria toxin at pH 5 are different from those seen at neutral pH. Trypsin-susceptible sites were identified by gel electrophoresis of the trypsin fragments, combined with electrophoresis and high pressure liquid chromatography of CNBr digests of trypsin-treated toxin. At neutral pH, the main sites of digestion are at the junction between the A- and B-fragments and near the NH2 terminus of the A-fragment. At pH 5.2, these sites are less efficiently cut, and new sites appear near the NH2 terminus of the B-fragment, in an amphipathic portion of the sequence. Thus, even in the absence of membranes, acid pH induces a significant conformational change in diphtheria toxin. This change involves burial of some previously accessible sites, exposure of previously inaccessible sites, and the formation of hydrophobic regions over an extensive portion of the polypeptide chain.

Affinity Labels↗

PubMed1988

Requirement of specific receptors for efficient translocation of diphtheria toxin A fragment across the plasma membrane.

The role of specific receptors in the translocation of diphtheria toxin A fragment to the cytosol and for the insertion of the B fragment into the cell membrane was studied. To induce nonspecific binding to cells, toxin was either added at low pH, or biotinylated toxin was added at neutral pH to cells that had been treated with avidin. In both cases large amounts of diphtheria toxin became associated with the cells, but there was no increase in the toxic effect. There was also no increase in the amount of A fragment that was translocated to the cytosol, as estimated from protection against externally added Pronase E. In cells where specific binding was abolished by treatment with 12-O-tetradecanoyl-phorbol 13-acetate, trypsin, or 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid, unspecific binding did not induce intoxication or protection against protease. This was also the case in untreated L cells, which showed no specific binding of the toxin. When Vero cells with diphtheria toxin bound to specific receptors were exposed to low pH, the cells were permeabilized to K+, whereas this was not the case when the toxin was bound nonspecifically at low pH or via avidin-biotin. The data indicate that the cell-surface receptor for diphtheria toxin facilitates both insertion of the B fragment into the cell membrane and translocation of the A fragment to the cytosol.

Animals↗

PubMed1987

Cytotoxicity of diphtheria toxin A fragment to toxin-resistant murine cells delivered by pH-sensitive immunoliposomes.

pH-sensitive immunoliposomes composed of dioleoylphosphatidylethanolamine and oleic acid (8:2 molar ratio) mediated the delivery of the cytotoxic fragment A of diphtheria toxin to the cytoplasm of target L-929 cells. Free fragment A, fragment A encapsulated in antibody-free liposomes, or fragment A encapsulated in pH-insensitive immunoliposomes was not effective in the inhibition of the cellular protein synthesis. pH-sensitive immunoliposomes containing diphtheria fragment A were not toxic to nontarget diphtheria-resistant A31 cells or to nontarget diphtheria-sensitive Vero cells. Pretreatment of target L-929 cells with the weak bases NH4Cl or chloroquine, agents which raise the endosome/lysosome pH, blocked the cytotoxic effect of the pH-sensitive immunoliposomes containing fragment A. Excess free antibody or excess empty pH-sensitive immunoliposomes also blocked the cytotoxic effect. Since it is known that fragment A alone cannot cross lipid membranes, the results of this study indicate that pH-sensitive immunoliposomes are able to release the toxin into the cytoplasm, probably by fusing with the endosome membrane following a receptor-mediated endocytosis of the immunoliposome.

Animals↗

PubMed1985

Diphtheria in Afghanistan--review of 155 cases.

During the 3-year study period, 155 culture-positive cases of diphtheria were reviewed at the Institute of Child Health, Kabul. They comprised 0.6% of hospital admissions due to medical disorders in our institute. About 80% of patients belonged to an age group of 1-10 years and only two patients were less than 1 year old. The male to female ratio was 1.3:1. There was no history of previous vaccination against diphtheria in 96.7% of patients. In the majority of patients faucial diphtheria was diagnosed (77.4%), followed by laryngeal (16.1%) an combined pharyngolaryngeal (6.5%). Clinical presentation was with a mild to moderate degree of fever, sore throat, cervical lymphadenopathy, toxaemia, tachycardia and a characteristic thick greyish-white membrane. The main early complications were laryngeal obstruction (35), myocarditis (18), shock (3), polyneuritis (3) and renal failure (2). The overall case fatality rate was 19.3%. Prognosis was unfavourable in patients with laryngeal diphtheria when there was a delay of more than 4 days before reaching the hospital and if there was a delay in relieving laryngeal obstruction by tracheostomy. Outcome was unrelated to the age of the patient.

Adolescent↗

PubMedDate not supplied

Hemolytic uremic syndrome associated with Corynebacterium diphtheria infection.

Although hemolytic uremic syndrome (HUS) is usually idiopathic, it follows a number of infections. The pathogenesis of post-infectious HUS is endothelial cell damage by either circulating endotoxin or exotoxin. Diphtheria exotoxin has never been implicated in HUS. We report HUS following diphtheria infection in a 9 yr old un-immunized white female admitted with a short history of sorethroat and thrombocytopenia. There were hemorrhages in sclera, gums and left tonsillar area and a grayish exudate on right tonsil. Laboratory values revealed Hgb 14.4 g/dl, decreasing to 7.6 g/dl, WBC/26,900 mm3, platelet count 7,000/mm3. Bone marrow examination revealed normal megakaryocytes. She was oliguric with BUN 214 mg/dl, serum creatinine 12.4 mg/dl and serum uric acid 19.2 mg/dl. Despite peritoneal dialysis, red cell and platelet transfusions and exchange transfusion she expired. A postmortem examination was refused. A throat culture done on admission grew corynebacterium species which was later confirmed to be toxigenic C. diphtheriae. Diphtheria exotoxin inactivates an enzyme in cytoplasm which is necessary for peptide chain elongation. This may have interfered with prostacyclin synthesis thereby allowing the development of HUS.

Blood Transfusion↗

PubMedDate not supplied

Diphtheria toxin sensitivity in a monochromosomal hybrid containing human chromosome 5.

Among the mouse-human hybrids prepared in our laboratory one clone was found to contain only human chromosome 5 with an integrated selectable marker. This monochromosomal hybrid was used to investigate different aspects related to the toxicity of diphtheria toxin (DT). The hybrid was as sensitive to diphtheria toxin as the human donor cells. The protective effect of NH4Cl against diphtheria toxin could be demonstrated in the hybrid and also in the mouse and human cell lines. The reversal of the protective NH4Cl effect at acid pH also could be demonstrated in all three cell types. Incubation of cells with 125I-diphtheria toxin at 37 degrees C in the presence of methylamine showed a time-dependent increase in specific association in the human and the hybrid but not in the mouse cell line. The results obtained for the first time on a stable monochromosomal hybrid suggest that chromosome 5 is both necessary and sufficient for the expression of DT sensitivity.

Ammonium Chloride↗

PubMed1984

Toxicity of ricin, diphtheria toxin and alpha-Amanitin for Acanthamoeba castellanii (1983).

Selective cytotoxic agents, highly specific antibody coupled to potent toxin molecules, could, theoretically, be useful in the treatment of protozoan infections. To examine this possibility we began to synthesize immunotoxins for a model protozoan system, Acanthamoeba castellanii. We report here the selection of a suitable toxic moiety for this system. alpha-Amanitin was toxic for the amoeba, effecting a 50% decrease in in vivo protein synthesis at approximately 20 microM. However, the chemical modification of alpha-amanitin necessary for its covalent attachment to antibody molecules reduced A. castellanii toxicity to the extent that alpha-amanitin is unsuitable as a toxic moiety in the synthesis of A. castellanii immunotoxins. Ricin and diphtheria toxin were non-toxic for the amoeba. In addition, A. castellanii cell-free protein biosynthesis, unlike that of any other eukaryotic system examined to date, was resistant to inhibition by ricin A chain. However, diphtheria toxin A chain inhibited A. castellanii cell-free protein synthesis by 50% at 2.5 nM. The inhibition of diphtheria toxin was NAD+ dependent, suggesting that ADP-ribosylation of EF-2 could be the cause of the inhibition as it is in mammalian cell lines. The toxicity of diphtheria toxin A chain is sufficient for its use in the synthesis of immunotoxins for A. castellanii.

Amanitins↗