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PubMedDate not supplied

Phage typing, an accessible and useful method in the epidemiological surveillance of diphtheria.

Within the framework of the measures for diphtheria prevention and control, phage typing of isolates is useful for epidemiological investigations in a disease focus and in general population. The identification of asymptomatic carriers of toxigenic C.diphtheriae and its eradication decrease the transmission rate of the disease. The study of the circulating phage types (6058) enabled us to demonstrate the frequency and distribution of the different phage types, toxigenic and nontoxigenic in Romania. With the current knowledge of the circulating phage types it can be concluded that imported cases of diphtheria have not occurred so far. The Romanian phage typing schemes are able to type isolates from overseas, sometimes through phage adaptation methods. Our phage typing schemes are also able to demonstrate any modifications in the phage sensitivity patterns of diphtheria.

Bacteriophage Typing↗
PubMed2000

Epidemic diphtheria in Ukraine, 1991-1997.

In 1991, Ukraine experienced a return of epidemic diphtheria after decades of control that had resulted in <40 sporadic cases reported every year. Increased incidence was first recorded in Kiev, Lviv, and Odessa. By 1993, the epidemic had spread to >50% of the oblasts (provinces) in the country, and by 1995, all regions were affected. In 1995, at the peak of the epidemic, >5,000 cases and >200 deaths were reported. As in Russia, >80% of these cases were diagnosed in persons 16-59 years old. In 1993, the government of Ukraine initiated a program of increased immunization among children and at-risk adults, and by 1995, a mass immunization strategy was adopted in an effort to arrest the epidemic, which was increasing exponentially. In 1996, the number of cases started to decrease, and data from 1998 indicate that the downward trend has continued. It is likely that the diphtheria epidemic in Ukraine started among children, who had been left vulnerable due to inadequate childhood immunizations, and then quickly spread to inadequately protected adults.

Adolescent↗
PubMed1991

[A comparative evaluation of the immunological efficacy of ADPT vaccine and ADT-M anatoxin in the immunization of children against diphtheria and tetanus].

Comparative study of the immunological effectiveness of adsorbed diphtheria-pertussis-tetanus (DPT) vaccine and adsorbed diphtheria-tetanus toxoid with reduced antigen content (adsorbed DT toxoid R) in the immunization of children, carried out in accordance with the vaccination schedule, was made. Immune response to the injection of adsorbed DPT vaccine was higher than after immunization with adsorbed DT toxoid R, as evidenced by antibody titers. It was probably due to differences in the number of injections constituting the course of immunization: it consisted of 3 injections and 1 booster injection for adsorbed DPT vaccine and 2 injections and 1 booster injection for adsorbed DT toxoid R. Immunization with adsorbed DPT vaccine produced immunity which was retained for a longer period. These results are indicative of the expediency of the primary immunization of children with adsorbed DT toxoid R introduced in three injections in order to ensure more stable and prolonged postvaccinal (mainly antidiphtheria) immunity.

Antibodies, Bacterial↗
PubMed2006

An improved mouse line for Cre-induced cell ablation due to diphtheria toxin A, expressed from the Rosa26 locus.

The means to specifically ablate cells inside of a living organism have recently been improved and facilitated by stable mouse lines, carrying conditional expression constructs for diphtheria toxin (DT) or diphtheria toxin receptor, that could be activated upon Cre-mediated recombination or the application of diphtheria toxin, respectively. We have lately described the R26:lacZ/DT-A line (Brockschnieder et al., 2004, Mol Cell Biol 24:7636-7642) in which a loxP-conditional DTA allele was introduced into the ubiquitously expressed Rosa26 locus. This strain allowed the ablation of a wide spectrum of cell types by crossing it to tissue specific Cre lines. Unexpectedly, homozygous (but not heterozygous) animals of the R26:lacZ/DT-A line developed some degenerative abnormalities in a variety of tissues. The defects were most probably caused by leaky expression of small amounts of toxin from the unrecombined lacZ(flox)DT-A cassette. Here we show that insertion of an additional transcriptional regulatory sequence (bovine growth hormone polyadenylation signal, bpA) following the lacZ open reading frame prevented the formation of any defects in homozygous mice. The modification did not affect the functionality of the lacZ(flox)DTA allele, as exemplified by the complete ablation of oligodendrocytes upon Cre-mediated recombination. The novel R26:lacZbpA(flox)DTA line is expected to greatly facilitate the reliable generation of cell type ablated mice.

Animals↗
PubMed1985

Diphtheria toxin resistance in human lymphocytes and lymphoblasts in the in vivo somatic cell mutation test.

It has been shown that circulating peripheral blood lymphocytes can be used for the enumeration of 6-thioguanine-resistant cells that presumably arise by mutation in vivo. This somatic cell mutation test has been studied in lymphocytes from human populations exposed to known mutagens and/or carcinogens. The sensitivity of the test could be further enhanced by including other gene markers, since there is evidence for locus-specific differences in response to mutagens. Resistance to diphtheria toxin (Dipr) seemed like a potential marker to incorporate into the test because the mutation acts codominantly, can readily be selected in human diploid fibroblasts and Chinese hamster cells with no evidence for cell density or cross-feeding effects, and can be assayed for in nondividing cells by measuring protein synthesis inhibition. Blood samples were collected from seven individuals, and fresh, cryopreserved, or Epstein-Barr virus (EBV)-transformed lymphocytes were tested for continued DNA synthesis (3H-thymidine, autoradiography) or protein synthesis (35S-methionine, scintillation counting). Both fresh and cryopreserved lymphocytes, stimulated to divide with phytohemagglutinin (PHA), continued to synthesize DNA in the presence of high doses of diphtheria toxin (DT). Similarly, both dividing (PHA-stimulated) and nondividing fresh lymphocytes carried on significant levels of protein synthesis even 68 hr after exposure to 100 flocculating units (LF)/ml DT. The findings were confirmed in cord blood lymphocytes, ruling out the possibility that diphtheria immunization could have led to a selection of Dipr lymphocytes. One lymphoblast line (EBV-transformed lymphocytes) showed a reduction in protein synthesis to 0.2% of controls only at 192 hr after exposure to 100 LF/ml. The results suggest that human T and B lymphocytes may not be as sensitive to DT protein synthesis inhibition as human fibroblast and Chinese hamster cells. For this reason, Dipr may not be a suitable marker for the somatic cell mutation test.

Cells, Cultured↗
PubMed1985

Entry of diphtheria toxin linked to concanavalin A into primate and murine cells.

Diphtheria toxin linked by a disulfide bridge to concanavalin A was highly toxic to HeLa S3 and Vero cells, as well as to murine L cells. The cells could be protected with alpha-methyl mannoside, indicating that the conjugate binds mainly through its concanavalin A moiety. Treatment of Vero cells with phospholipase C, TPA (12-O-tetradecanoylphorbol-13-acetate), and vanadate, which strongly reduce the ability of the cells to bind free diphtheria toxin, had little protective effect against the conjugate, whereas SITS (L-acetamido-4'-isothiocyano-stilbene-2,2'disulfonic acid), which inhibits diphtheria toxin binding, as well as the subsequent entry, protected Vero cells, but not L cells. Both types of cells are protected against the conjugate by NH4Cl and monensin, indicating that an acidified compartment is necessary for entry into the cytosol. Exposure of cells, bound with surface conjugate, to low pH induced entry of the toxin into Vero cells, but not into L Cells. Phospholipase C, TPA, and vanadate did not protect L cells against the conjugate. It is concluded that toxin in the conjugate enters L cells by a route which involves low pH, but which is not identical to that in Vero cells.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed1997

Comparison of high-resolution structures of the diphtheria toxin repressor in complex with cobalt and zinc at the cation-anion binding site.

The diphtheria toxin repressor (DtxR) from Corynebacterium diphtheriae is a divalent-metal activated repressor of chromosomal genes responsible for siderophore-mediated iron-uptake and of a gene on several corynebacteriophages that encodes diphtheria toxin. Even though DtxR is the best characterized iron-dependent repressor to date, numerous key properties of the protein still remain to be explained. One is the role of the cation-anion pair discovered in its first metal-binding site. A second is the reason why zinc exhibits its activating effect only at a concentration 100-fold higher than other divalent cations. In the presently reported 1.85 A resolution Co-DtxR structure at 100K, the sulfate anion in the cation-anion-binding site interacts with three side chains that are all conserved in the entire DtxR family, which points to a possible physiological role of the anion. A comparison of the 1.85 A Cobalt-DtxR structure at 100K and the 2.4 A Zinc-DtxR structure at room temperature revealed no significant differences. Hence, the difference in efficiency of Co2+ and Zn2+ to activate DtxR remains a mystery and might be hidden in the properties of the intriguing second metal-binding site. Our studies do, however, provide a high resolution view of the cationanion-binding site that has most likely evolved to interact not only with a cation but also with the anion in a very precise manner.

Bacterial Proteins↗
PubMed1998

Expression of mutant dynamin protects cells against diphtheria toxin but not against ricin.

Diphtheria toxin is believed to enter sensitive mammalian cells via receptor-mediated endocytosis from clathrin-coated pits, while ricin can enter via both clathrin-dependent and clathrin-independent endocytosis. The present study has confirmed this by determining the toxin sensitivity of COS-7y cells which were transiently overexpressing a trans dominant negative mutant of dynamin, a GTPase required for the budding of clathrin-coated vesicles from the plasma membrane. Cells overexpressing wild-type dynamin showed normal receptor-mediated endocytosis of transferrin and remained sensitive to both diphtheria toxin and ricin. Cells overexpressing a mutant dynamin defective in GTP binding and hydrolysis were unable to endocytose transferrin and were protected against diphtheria toxin, but they remained completely sensitive to ricin intoxication. Treating non-transfected cells or cells overexpressing mutant dynamin with nystatin caused a redistribution of the caveolae membrane marker protein VIP21-caveolin from the cell surface to intracellular locations, but did not affect their sensitivity to ricin. The redistribution of caveolin seen after nystatin treatment may reflect the disappearance of caveolae. If this is the case, caveolae are not responsible for the endocytosis of ricin. An alternative clathrin-independent route may operate for ricin, since cellular uptake, intracellular transport, and translocation into the cytosol remain unaffected when clathrin-dependent endocytosis is effectively blocked.

Animals↗
PubMed1999

Crystal structure of a cobalt-activated diphtheria toxin repressor-DNA complex reveals a metal-binding SH3-like domain.

The diphtheria toxin repressor (DtxR) is the prototype of a family of iron-dependent regulator (IdeR) proteins, which are activated by divalent iron and bind DNA to prevent the transcription of downstream genes. In Corynebacterium diphtheriae, DtxR regulates not only the expression of diphtheria toxin encoded by a corynebacteriophage, but also of components of the siderophore-mediated iron-transport system. Here we report the crystal structure of wild-type DtxR, a 226 residue three-domain dimeric protein, activated by cobalt and bound to a 21 bp DNA duplex based on the consensus operator sequence. Two DtxR dimers surround the DNA duplex which is distorted compared to canonical B -DNA. The SH3-like third domain interacts with the metal at site 1 via the side-chains of Glu170 and Gln173, revealing for the first time a metal-binding function for this class of domains. The SH3-like domain is also in contact with the DNA-binding first domain and with the second, or dimerization, domain. The DNA-binding helices in the first domain are shifted by 3 to 5 A when compared to the apo-repressor, and fit into the major groove of the duplex bound. These shifts are due to a hinge-binding motion of the DNA-binding domain with respect to the dimerization domains of DtxR. The third domain might play a role in regulating this hinge motion.

Bacterial Proteins↗
PubMed1995

Targeting diphtheria toxin to growth factor receptors.

Biochemical, genetic and X-ray crystallographic analysis of diphtheria toxin have demonstrated that the native toxin is composed of three structural domains that function in an ordered fashion to intoxicate a eukoryotic cell. With the knowledge that, if delivered to the cytosol, a single molecule of the catalytic domain is lethal for the cell, we have used recombinant DNA methods to genetically replace the native toxin receptor binding domain with a series of growth factors. The resulting diphtheria toxin-related cytokine fusion proteins, or fusion toxins bind to their respective receptors, are internalized by receptor-mediated endocytosis, and efficiently eliminate target cell populations by the adenosine diphosphate ribosylation of elongation factor 2. Based upon the results of preclinical studies, DAB486IL-2, DAB389IL-2 and DAB389EGF have, or are in the process of being evaluated in Phase I/II clinical trials. To date, administration of the diphtheria toxin-based fusion proteins targeted toward the high affinity IL-2 receptor have been found to be safe, well tolerated, and capable of inducing remission in refractory hematologic malignancies.

Diphtheria Toxin↗
PubMed1975

Contractility and ultrastructure of cardiac muscle of guinea pigs treated with diphtheria toxin.

The development of tension and the ultrastructure of cardiac papillary muscle of normal guinea pigs were compared to guinea pigs receiving lethal doses of diphtheria toxin. The maximal isometric force of the papillary muscles at various levels of resting tension indicated no significant difference between the control and the diphtheritic animals. Neither did the sarcomere lengths of papillary muscles, fixed at various levels of tension, show any significant difference between these two groups. Electronmicroscopy in diphtheritic animals showed intact myofilaments but marked dilatation of the T and L system as well as pathologic fat deposits adjacent to the subsarcolemma and the T system. The results, therefore, suggest that diphtheria toxin acts on the T and L system, but does not affect structure and function of the myofilaments in the acute stage of diphtheria intoxication.

Actomyosin↗
PubMed1977

Regional mapping of human genes for hexosaminidase B and diphtheria toxin sensitivity on chromosome 5 using mouse X human hybrid cells.

Mouse 3T3 (TK-) cells were fused to human leukocytes containing a balanced translocation [ins(3;5) (q27;q13q15)] in which part of the long arm of a chromosome 5 has been inserted into the long arm of a chromosome 3. Two independent, primary hybrid clones (XVI-10C;XVI-18A) retained the deleted chromosome 5 [del(5) (q13q15)] translocation product and were informative for regional mapping on chromosome 5 of genes involved in expression of hexosaminidase B (HEXB) and diphtheria toxin sensitivity (DTS). Both XVI-10C and XVI-18A clones were sensitive to diphtheria toxin. Toxin-resistant derivatives of these clones (XVI-10C DTR; XVI-18A DTR) were analyzed for chromosome content and expression of Hex B activity, as were XVI-10C and XVI-18A cells which had not been exposed to diphtheria toxin. The results of this study provide evidence for localization of DTS to region 5q15 leads to 5 qter on the long arm of chromosome 5, and localization of HEXB to region 5pter leads to 5q13.

Chromosome Mapping↗
PubMed1987

An outbreak of diphtheria among Swedish alcoholics.

After 25 years without any indigenous cases of diphtheria in Sweden, an outbreak occurred in the city of Göteborg, during 1984 to 1986. A group of alcoholics constituted the reservoir of Corynebacterium diphtheriae. The outbreak included 13 clinical cases and 65 carriers. The death-to-case ratio and the complication rate among the clinical cases was high, with three fatal cases and six patients developing reversible paralyses. The fatal cases had no history of previous immunization. The outbreak demonstrates the necessity of a good vaccination status to diphtheria, also in countries where the disease was thought to have been eradicated.

Adolescent↗
PubMedDate not supplied

Serum antibodies to the components of diphtheria-tetanus-pertussis vaccine in Polish children related to vaccination status.

In Poland vaccination against diphtheria, tetanus and pertussis (DTP) is recommended from 2-3 months of age. Three doses at approximately 6-week intervals are given. A booster dose of DTP is given at 19-24 months and boosters of DT at 6 and 14 years. In this study serum samples were obtained from 166 Polish children aged 2 weeks to 14 years. Vaccination status was verified from the children's Health Books. Antibodies were determined against pertussis toxin, filamentous hemagglutinin (FHA), pertactin, tetanus toxoid and diphtheria toxin. Antibodies of maternal original against all five antigens were detected in almost all sera from infants not yet vaccinated. Antibody levels increased with the number of vaccinations given. Children who had recently received the fourth vaccination had the highest antibody levels. Antibody levels decreased with time after the fourth vaccination for all antibodies except FHA. It was concluded that the Polish whole cell pertussis vaccine stimulates antibodies against pertussis toxin, FHA and pertactin, but that antibodies against FHA probably also are stimulated by cross-reacting antigens. Diphtheria toxin and tetanus toxoid antibodies were above protective levels in all vaccinated children, but the long-term decreases justify the booster dose at 14 years. Twenty-five of 166 children (15%) had a vaccination status which deviated from recommendations demonstrating a need to increase the vaccination rate.

Adhesins, Bacterial↗
PubMed1990

Action of diphtheria toxin does not depend on the induction of large, stable pores across biological membranes.

Vero cells exposed to diphtheria toxin at pH 4.5 leak monovalent cations but not amino acids or phosphorylated metabolites; affected cells do not take up trypan blue. Monovalent cation leakage is inhibited by 1 mM Cd2+, but not by 1 mM Zn2+ or Ca2+. Cd2+ blocks calcein leakage from liposomes and closes diphtheria toxin-induced channels in lipid bilayers. It is concluded that translocation of the A fragment of diphtheria toxin across biological membranes does not depend on the formation of large stable pores, but that small Cd2(+)-sensitive pores may play a role.

Animals↗
PubMed1996

Relapsing acute encephalopathy: a complication of diphtheria-tetanus-poliomyelitis immunization in a young boy.

UNLABELLED: Neurological complications of immunizations are rare. We report the case of relapsing acute encephalitis in a boy after two subsequent diphtheria-tetanus-poliomyelitis vaccinations. First the clinical signs were those of acute disseminated encephalitis. During the second episode, the boy experienced optic neuritis. Recovery was complete after both events. Because of the close temporal relationship of both these demyelinating episodes with the immunizations, we favour a cause and effect relationship. CONCLUSION: The observation of a 7-year-old boy who developed relapsing acute encephalitis after two diphtheria-tetanus-poliomyelitis vaccinations and a similar case in the literature suggests that this neurological manifestation may occur as a very rare complication of diphtheria-tetanus-poliomyelitis vaccination.

Cerebellar Cortex↗
PubMed2005

Reduced-antigen-content-diphtheria-tetanus-acellular-pertussis and inactivated polio vaccine as a booster for adolescents 10 to 14 years of age.

UNLABELLED: High rates of pertussis disease in adolescents suggest that additional boosting against pertussis would be beneficial. A combined acellular-pertussis-containing booster vaccine (dTpa-IPV; Boostrixtrade mark Polio, n =440) was compared to separately administered dTpa (Boostrixtrade mark) and inactivated polio virus (IPV; Imovax Polio((R)), n =219), and to DTPa-IPV (Infanrixtrade mark IPV, n =111) vaccine in a partially blind, randomised controlled trial in 10-14 year olds. One month after vaccination, seroprotection/seropositivity rates for all antigens were similar for all groups. Although pertussis and diphtheria antibody geometric mean antibody concentrations were higher after DTPa-IPV, all subjects had protective antibodies against diphtheria, tetanus and polio, and at least 97% had a vaccine response to pertussis antigens. Reactogenicity of dTpa-IPV was comparable to dTpa + IPV, but dTpa-IPV was generally better tolerated than DTPa-IPV. CONCLUSION: The combined reduced-antigen-content-diphtheria-tetanus-acellular-pertussis and IPV vaccine is immunogenic and well tolerated when administered to adolescents and could be used to improve the control of pertussis disease in this age group.

Adolescent↗
PubMed1999

Local reactions and IgE antibodies to pertussis toxin after acellular diphtheria-tetanus-pertussis immunization.

Local reactions and pertussis toxin specific immunoglobulin E antibodies (PT-IgE) were investigated in healthy children following primary and booster immunization with a combined diphtheria tetanus acellular pertussis vaccine (DTPa) including pertussis toxin, filamentous haemagglutinin and pertactin. A primary series of DTPa was administered to 150 infants, and 104 of them received a booster dose of DTPa combined with inactivated polio vaccine at 2 years of age. PT-IgE was measured in serum samples from 72 children using a modified nitrocellulose RAST. Primary immunization was associated with low incidence of local reactions (1%-5%). After the booster dose 21% of children had a local reaction >/=20 mm. Local reactions after the booster dose tended to be more common in children who had experienced reaction at primary immunization. PT-IgE was detected in 18% and 86% of children following primary and booster vaccinations, respectively. Allergic and non-allergic children did not differ in PT-IgE responses. After primary immunization, elevated PT-IgE levels were found more often in children with a family history of allergy than in those without known allergy in the family. Children with local reactions had significantly higher pre- and post-booster PT-IgE levels and median post-booster pertactin IgG and diphtheria-IgG levels than children without local reactions. Conclusion Acellular pertussis immunization induces IgE antibodies to pertussis toxin, especially after booster vaccination. The higher median pre- and post-booster levels of pertussis toxin specific immunoglobulin E and post-booster levels of IgG to pertactin and diphtheria in children with local side-effects reflect a multifactorial immunological mechanism of such reactions.

Child, Preschool↗