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PubMed2006

Association between cardiac disorders and a decades-previous history of diphtheria.

A long, prior history of diphtheria is common among middle-aged and elder European adults. The aim of the present study was to determine whether the risk of reduced ventricular function and impaired intraventricular conduction is increased in individuals with a history of diphtheria. A study population of 2,480 subjects (1,222 women) aged 45 years or older who were recruited for the Study of Health in Pomerania were available for the present analyses. Left ventricular function was assessed by echocardiography. Intraventricular conduction blocks were diagnosed using electrocardiograms. Multivariable analyses revealed that individuals with a history of diphtheria had neither an increased odds for reduced fractional shortening (OR 1.21, 95% CI 0.69-2.11; p=0.51) nor an increased odds for intraventricular conduction blocks (OR 0.90, 95% CI 0.55-1.46; p=0.67). However, regression models revealed two-way interactions between the exposure variable and hypertension with respect to both endpoints. A history of diphtheria increased the odds for both endpoints in normotensive but not in hypertensive individuals. The findings show that a history of diphtheria several decades previously in a patient is a risk marker for reduced cardiac function and impaired intraventricular conduction in individuals at low risk for these disorders.

Adult↗
PubMed1980

A hybrid toxin containing fragment A from diphtheria toxin linked to the B protomer of cholera toxin.

We have constructed and characterized a hybrid toxin containing the A chain of diphtheria toxin linked via a disulfide bridge to the B protomer of cholera toxin. Cholera toxin B protomer, previously derivatized with 4-5 cystaminyl groups per pentameric protomer, was reacted with reduced diphtheria toxin chain A to give the desired hybrid, containing an average of 2 molecules of diphtheria toxin chain A per cholera toxin B protomer. A concentration of 0.3 nM hybrid inhibited protein synthesis by 50% in 24 h in several cultured cell lines; thus the hybrid was about 10-fold more toxic than of a (diphtheria toxin chain A)-SS-(concanavalin A) conjugate described previously. Evidence was obtained that toxicity of the hybrid was dependent on the functional contributions of both the diphtheria toxin chain A and cholera toxin B protomer moieties.

Animals↗
PubMed1990

Response to a Haemophilus influenzae type b diphtheria CRM197 conjugate vaccine in children with a defect of antibody production to Haemophilus influenzae type b polysaccharide.

A defect in antibody response to immunization with Haemophilus influenzae type b (Hib) capsular polysaccharide vaccine has been reported in children with recurrent infections and normal immunoglobin levels. We identified 15 children, aged 2 to 6 years, with this defect, and we evaluated their response to immunization with an Hib capsular oligosaccharide diphtheria CRM197 protein-conjugate vaccine (HbOC). The children received a series of three vaccines: HbOC at 0 and 8 weeks, and the Hib polysaccharide vaccine at 16 weeks. Levels of antibody to the Hib capsular polysaccharide (polyribosyl ribitol phosphate, PRP) and to diphtheria toxoid were obtained before and 4 weeks after each vaccination. The geometric mean serum anti-PRP concentration was 0.17 microgram/ml before immunization and 29.3 micrograms/ml after the second HbOC immunization (week 12). All 15 children had postvaccination anti-PRP antibody levels greater than 1.0 microgram/ml after receiving the second HbOC (week 12). In addition, booster responses were observed after the second Hib conjugate in 13 of the patients and after the Hib polysaccharide in four of the patients. All patients with low preimmunization diphtheria titers had a response to the diphtheria toxoid. These results suggest that conjugation of Hib polysaccharide with diphtheria CRM197 overcomes the defective antibody response to Hib oligosaccharide in children who are initially observed with recurrent infections and inability to respond to the Hib polysaccharide vaccine.

Antibodies, Bacterial↗
PubMed2004

Electrocardiographic abnormalities in patients with diphtheria: a prospective study.

PURPOSE: To determine the incidence of and risk factors for electrocardiographic (ECG) abnormalities in adults with diphtheria. METHODS: A prospective study was conducted involving 122 adult patients with respiratory tract diphtheria. Diphtheria was confirmed by isolation of a toxin-producing strain of Corynebacterium diphtheriae. Patients had serial clinical evaluations and ECGs for a minimum of 21 days. RESULTS: Cardiac involvement was detected in 25 (28%) of 88 evaluable patients, with a median time from symptom onset to an abnormal ECG of 9 days (range, 4 to 24 days). In a logistic regression analysis, age (odds ratio [OR] = 4.1; 95% confidence interval [CI]: 1.6 to 11.0), shared accommodation (OR = 2.9; 95% CI: 1.0 to 8.6), fever (OR = 4.2; 95% CI: 1.1 to 16.6), and extensive respiratory tract infection with subcutaneous edema (OR = 7.0; 95% CI: 1.2 to 42.2) were independent risk factors for cardiac involvement. CONCLUSION: Cardiac involvement is a common complication of respiratory tract infection with C. diphtheriae, and occurs more often among older patients, those with lower socioeconomic status, and those with severe respiratory tract involvement.

Adolescent↗
PubMed1997

Differential toxicity of ricin and diphtheria toxin for bloodstream forms of Trypanosoma brucei.

The cytotoxicity of ricin and diphtheria toxin was studied in culture-adapted bloodstream forms of Trypanosoma brucei. Although ricin is endocytosed at a rate comparable to that of other internalized macromolecules, it is nontoxic to bloodstream-form trypanosomes. The resistance lies partly in low susceptibility of the targeted ribosomes: T. brucei cell-free protein biosynthesis is only partially inhibited by ricin A chain. In addition, ricin is degraded before it reaches the ribosomes, as the toxin is delivered to lysosomes. In contrast, diphtheria toxin shows similar cytotoxicities for bloodstream-form trypanosomes and mouse myeloma cells. Both trypanosome and myeloma cells are more than 1000-fold less sensitive to the action of the toxin than most other mammalian cell lines, although nicked reduced diphtheria toxin inhibits cell-free protein synthesis of T. brucei and myeloma cells to the same extent as that of a rabbit reticulocyte lysate. The effect of diphtheria toxin on T. brucei in vitro translation is NAD+ dependent, suggesting that ADP-ribosylation of elongation factor 2 could be the cause of the inhibition as it is in mammalian cells. Thus, the toxic moiety of diphtheria toxin is suitable for preparation of cell-type-specific cytotoxic reagents directed towards trypanosomes.

Animals↗
PubMed1995

Structure of the isolated catalytic domain of diphtheria toxin.

The structure of the isolated catalytic domain of diphtheria toxin at pH 5.0 was determined by X-ray crystallography at 2.5 A resolution and refined to an R-factor of 19.7%. The domain is bound to its endogenous inhibitor adenylyl(3'-->5')uridine 3'-monophosphate (ApUp). The structure of this 190-residue domain, which was expressed in and isolated from Escherichia coli, is essentially identical to the structure of the catalytic domain within whole diphtheria toxin determined at pH 7.5. However, there are two adjacent surface loops (loop 66-78 and loop 169-176) that exhibit clear differences when compared to the structure of the catalytic domain in whole diphtheria toxin. Although both loops are at the surface of the protein and are relatively flexible, the chain trace is well-defined in the electron density. The main structural difference is the closer approach of loops 66-78 and 169-176. We ascribe this structural change mainly to the absence of the neighboring transmembrane domain in the isolated catalytic domain as compared to whole diphtheria toxin. We suggest that this change represents the first step of the structural transition from the catalytic domain in whole diphtheria toxin to the translocated form of the domain. The changes are described in detail, and their implications for membrane translocation are discussed.

Binding Sites↗
PubMed2000

Corynebacterium diphtheriae genes required for acquisition of iron from haemin and haemoglobin are homologous to ABC haemin transporters.

Corynebacterium diphtheriae and Corynebacterium ulcerans use haemin and haemoglobin as essential sources of iron during growth in iron-depleted medium. C. diphtheriae and C. ulcerans mutants defective in haemin iron utilization were isolated and characterized. Four clones from a C. diphtheriae genomic library complemented several of the Corynebacteria haemin utilization mutants. The complementing plasmids shared an approximately 3 kb region, and the nucleotide sequence of one of the plasmids revealed five open reading frames that appeared to be organized in a single operon. The first three genes, which we have termed hmuT, hmuU and hmuV, shared striking homology with genes that are known to be required for haemin transport in Gram-negative bacteria and are proposed to be part of an ABC (ATP-binding cassette) transport system. The hmuT gene encodes a 37 kDa lipoprotein that is associated with the cytoplasmic membrane when expressed in Escherichi coli and C. diphtheriae. HmuT binds in vitro to haemin- and haemoglobin-agarose, suggesting that it is capable of binding both haemin and haemoglobin and may function as the haemin receptor in C. diphtheriae. This study reports the first genetic characterization of a transport system that is involved in the utilization of haemin and haemoglobin as iron sources by a Gram-positive bacterium.

ATP-Binding Cassette Transporters↗
PubMed1978

Diphtheria toxin has the properties of a lectin.

The inhibition of protein synthesis in Chinese hamster V79 cells by diphtheria toxin is antagonized by the lectins concanavalin A, succinylated concanavalin A, and wheat germ agglutinin but not by Proteus vulgaris phytohemagglutinin or abrus agglutinin. The effects of concanavalin A and wheat germ agglutinin are reversed by methyl alpha-mannoside and N-acetylglucosamine, respectively. The inhibition of diphtheria toxin as a function of concanavalin A concentration fits a model of competitive inhibition with an apparent dissociation constant for concanavalin A of 3 X 10(-8) M. These results suggest that the diphtheria toxin receptor may be an oligosaccharide. To test this hypothesis, we screened several oligosaccharides for the ability to inhibit diphtheria toxin. The cell wall polysaccharide of Salmonella cholera suis and the ovalbumin glycopeptide were effective inhibitors. These studies suggest that diphtheria toxin may have the oligosaccharide binding properties of a lectin with specificity for N-acetylglucosamine and mannose.

Cell Line↗
PubMed1990

Diphtheria toxin mutant selectively kills cerebellar Purkinje neurons.

CRM107 (crossreacting material 107), a double point mutant of diphtheria toxin that lacks receptor-binding activity, specifically kills cerebellar Purkinje cells in vivo. After injection into guinea pig cerebrospinal fluid, CRM107 (0.9 micrograms) and CRM107-monoclonal antibody conjugates (10 micrograms) kill up to 90% of the total Purkinje cell population with no detectable toxicity to other neurons. Animals exhibit ataxia, tremor, and abnormalities of posture and tone. Native diphtheria toxin, ricin, and ricin A chain do not cause ataxia and do not reduce the Purkinje cell population after intrathecal injection into guinea pigs at toxic or maximally tolerated doses. However, in rats, which will tolerate higher doses of diphtheria toxin than guinea pigs, Purkinje cells can be killed by both CRM107 and diphtheria toxin. A truncated mutant of diphtheria toxin, called CRM45, can also cause Purkinje cell killing but has additional toxicity not seen with CRM107. Animals treated with intrathecal CRM107 or CRM107 linked to antibodies may serve as models for Purkinje cell loss in a broad spectrum of human diseases and may be used to further study cerebellar physiology. Understanding the basis for the Purkinje cell sensitivity to CRM107 may illuminate other causes of Purkinje cell loss.

Animals↗
PubMed1981

Fetal immune response following maternal diphtheria during early pregnancy.

A pregnant Sudanese woman contracted pharyngeal diphtheria during the first trimester of gestation. She had a severe diphtheritic toxaemia and paralysis of all four limbs but made a full recovery from these manifestations. Pregnancy, apart from vaginal bleeding, was not interrupted. At term she was delivered of a female baby who was physically normal but had a very high level of IgA in cord blood. Diphtheria in adults is a rare disease and the occurrence of diphtheria in a pregnant woman has not, as yet, been reported. Accordingly it is not known how fetal growth and development progress in the presence of diphtheria toxin in the maternal circulation. Similarly the effects on fetal immune responses of an acute maternal infection like diphtheria occurring in early pregnancy are not known.

Adult↗
PubMed1979

Biochemical and genetic characterization of three hamster cell mutants resistant to diphtheria toxin.

We describe here three different hamster cell mutants which are resistant to diphtheria toxin and which provide models for investigating some of the functions required by the toxin inactivates elongation factor 2 (EF-2). Cell-free extracts from mutants Dtx(r)-3 was codominant. The evidence suggests that the codominant phenotype is the result of a mutation in a gene coding for EF-2. The recessive phenotype might arise by alteration of an enzyme which modifies the structure of EF-2 so that it becomes a substrate for reaction with the toxin. Another mutant, Dtx(r)-2, contained EF-2 that was sensitive to the toxin and this phenotype was recessive. Pseudomonas aeruginosa exotoxin is known to inactivate EF-2 as does diphtheria toxin and we tested the mutants for cross-resistance to pseudomonas exotoxin. Dtx(r)-1 and Dtx(r)-3 were cross-resistant while Dtx(r)-2 was not. It is known that diphtheria toxin does not penetrate to the cytoplasm of mouse cells and that these cell have a naturally occurring phenotype of diphtheria toxin resistance. We fused each of the mutants with mouse 3T3 cells and measured the resistance. We fused each of the mutants with mouse 3T3 cells and measured the resistance of the hybrid cells to diphtheria toxin. Intraspecies hybrids containing the genome of mutants Dtx(r)-1 and Dtx(r)-3 had some resistance while those formed with Dtx(r)-2 were as sensitive as hybrids derived from fusions between wild-type hamster cells and mouse 3T3 cells.

Animals↗
PubMed1999

Simultaneous vitamin A administration at routine immunization contact enhances antibody response to diphtheria vaccine in infants younger than six months.

A randomized, double-blind, placebo-controlled trial was conducted to evaluate the effect of simultaneous vitamin A supplementation and diphtheria, pertussis and tetanus (DPT) vaccination on the antibody levels. Infants aged 6-17 wk (n = 56) were randomly given 15 mg oral vitamin A or placebo at the time of their DPT immunization. Three such doses were given at monthly intervals. Immunoglobulin (Ig) G antibodies to diphtheria, pertussis and tetanus were assayed on enrollment and 1 mo after the third dose. Baseline antibody concentrations to diphtheria, pertussis and tetanus did not differ between the vitamin A-supplemented and placebo-treated groups. The postdose antibody to diphtheria level was significantly greater in the vitamin A than in the placebo-treated group. The geometric mean +/- SEM antibody levels (mg/L) were 22.9 +/- 1.2 and 11.0 +/- 1.3 in the vitamin A and placebo groups, respectively (P = 0.029). The postsupplementation concentrations of antibodies to pertussis and tetanus did not differ between the two groups. These results suggest that antibody response to diphtheria vaccination was potentiated by simultaneous vitamin A administration and DPT immunization.

Antibodies, Bacterial↗
PubMed1981

Studies on the role of a nucleoside-phosphate-binding site of diphtheria toxin in the binding of toxin to Vero cells or liposomes.

Using Fab antibody fragments directed against protein crm 45 (non-toxic cross-reacting material serologically-related to diphtheria toxin mutant protein, the product of a non-sens mutation in the diphtheria toxin gene) or the B 45 domain of this molecule (the remaining portion of the toxin B fragment present in protein crm 45)., we have shown that the diphtheria toxin polyphosphate-binding site (P site) [Lory and Collier (1980) Proc. Natl Acad. Sci. USA, 1, 267-271], evidenced by the ability of the toxin to bind ATP, is affected upon incubation of this protein with the Fab fragment of anti-protein (crm 45) IgG but not with the Fab fragment of anti-polypeptide (B 45) IgG. After incubation with an excess of the Fab fragment of anti-polypeptide (B 45) IgG, 125I-labeled toxin does not bind to toxin-sensitive Vero cells. We therefore suggest that the P site is not by itself the binding domain of diphtheria toxin to the cell membrane receptor and that the region of the toxin molecule devoted to this particular activity overlapped probably on the B 45 polypeptide. In contrast with the results obtained by Alving et al. (Proc. Natl Acad. Sci. USA, 1980, 4, 1986-1990) with or without a functional P site, diphtheria toxin is able to bind liposomes. However interaction with phospholipid vesicles with toxin is blocked upon incubation of the protein with the Fab fragment of anti-polypeptide (B 45) IgG. Our data indicate that the P site of toxin does not participate in the ability of this molecule to bind liposomes.

Adenosine Triphosphate↗
PubMed1996

Synthesis, cytotoxic properties and effects on early and late gene induction of a chimeric diphtheria toxin-leukemia-inhibitory factor protein.

Leukemia-inhibitory factor (LIF) is a neuropoietin able to regulate the differentiation and the survival of many cell types, which include some neuronal populations. The present study describes the genetic construction, expression, purification and properties of a diphtheria-toxin-related LIF gene fusion in which the native receptor-binding domain of diphtheria toxin was replaced with a gene encoding human LIF. The fusion protein expressed from the chimeric tox gene was designated DT-(1-389)-LIF-(2-184)-peptide. This fusion protein has a deduced molecular mass of 65980 Da and is formed by fusion of the first 389 amino acids of diphtheria toxin to amino acids 2-184 of mature human LIF, using a linker of 34 amino acids that includes six consecutive histidine residues. The latter span allows for single-step purification of the fusion protein by Ni(2+)-resin affinity chromatography. This linker provides a high degree of flexibility between the diphtheria toxin and LIF domains, thereby permitting aggregation-free refolding of the chimeric protein while bound to the affinity column. Both LIF and DT-(1-389)-LIF-(2-184)-peptide induced the phosphorylation of CLIP1 and CLIP2 in LIF-responsive neuroblastoma SH-N-BE cells. DT-(1-389)-LIF-(2-184)-peptide was selectively cytotoxic for cultured neuroblastoma cells bearing the LIF receptor, and for sympathetic neurons. The cytotoxic action of DT-(1-389)-LIF-(2-184)-peptide, like that of native diphtheria toxin, required receptor-mediated endocytosis, passage through an acidic compartment, and delivery of an ADP-ribosyltransferase to the cytosol of target cells. The latter point was confirmed by the fact that, while both LIF and DT-(1-389)-LIF-(2-184)-peptide increased c-fos mRNA expression in SH-N-BE cells, only LIF induced proenkephalin and c-fos promoter activities in cells transiently transfected with c-fos-chloramphenicol acetyltransferase and proenkephalin-chloramphenicol acetyltransferase fusion genes. Mutational analysis suggested that the C-terminal helix (helix D) of human LIF may, in part, constitute or contribute to the active site for LIF receptor binding and cell activation. The cytotoxic properties of DT-(1-389)-LIF-(2-184)-peptide may be useful in selectively depleting neuronal and immune cell populations that express the LIF beta receptor.

Amino Acid Sequence↗
PubMed1992

Immunity against diphtheria and tetanus in human immunodeficiency virus-infected Danish men born 1950-59.

To evaluate the possible need for vaccination against diphtheria and tetanus of patients infected with the human immunodeficiency virus (HIV), antibodies were measured in blood samples from 78 Danish HIV-infected men, born 1950-59, who could be expected to have received primary vaccination before they contracted the HIV infection. No patients (95% confidence interval: 0-4) had tetanus antibodies below the protective level, whereas 24 of the 78 patients (16-33) were unprotected against diphtheria. In the background population of the same age group and sex, 5% and 10% have been found unprotected against tetanus and diphtheria, respectively. No relationship between disease stages and antibody levels could be found. Neither was there any difference between patients with normal and reduced numbers of CD4+ lymphocytes. From 25 patients two blood samples were taken at an interval of at least one year. Anti-tetanus titres showed a decrease comparable to that found in the background population, whereas the change in anti-diphtheria titres was more variable with rising antibody concentrations in nine patients. The fall off in antibodies did not increase with progression of the disease. It is concluded that HIV-positive younger men who have followed the vaccination program against tetanus prior to the HIV infection can be expected to be protected, whereas revaccination against diphtheria must be considered.

Adult↗
PubMed1987

Mutations in diphtheria toxin separate binding from entry and amplify immunotoxin selectivity.

Monoclonal antibodies linked to toxic proteins (immunotoxins) can selectively kill some tumor cells in vitro and in vivo. However, reagents that combine the full potency of the native toxins with the high degree of cell type selectivity of monoclonal antibodies have not previously been designed. Two heretofore inseparable activities on one polypeptide chain of diphtheria toxin and ricin account for the failure to construct optimal reagents. The B chains (i) facilitate entry of the A chain to the cytosol, which allows immunotoxins to efficiently kill target cells, and (ii) bind to receptors present on most cells, which imparts to immunotoxins a large degree of non-target cell toxicity. This report identifies point mutations in the B polypeptide chain of diphtheria toxin that block binding but allow cytosol entry. Three mutants of diphtheria toxin have 1/1,000 to 1/10,000 the toxicity and 1/100 to 1/8,000 the binding activity of diphtheria toxin. Linking of either of two of the inactivated mutant toxins (CRM103, Phe508; CRM107, Phe390, Phe525) to a monoclonal antibody specific for human T cells reconstitutes full target-cell toxicity--indistinguishable from that of the native toxin linked to the same antibody--without restoring non-target cell toxicity. This separation of the entry function from the binding function generates a uniquely potent and cell type-specific immunotoxin that retains full diphtheria toxin toxicity, yet is four to five orders of magnitude less toxic than the native toxin is to nontarget cells.

Animals↗
PubMed2003

Effects of iron limitation on adherence and cell surface carbohydrates of Corynebacterium diphtheriae strains.

Iron limitation may cause bacterial pathogens to grow more slowly; however, it may also stimulate these microorganisms to produce greater tissue damage, given that many virulence factors are controlled by the iron supply in the environment. The present study investigated the influence of low iron availability on the expression of proteins and surface sugar residues of two toxigenic strains of Corynebacterium diphtheriae subsp. mitis and evaluated their adherence to human group B erythrocytes and HEp-2 cells. A comparison was made between bacteria grown in (i) Trypticase soy broth (TSB), (ii) TSB treated with dipyridyl to deplete free iron, and (iii) TSB enriched with FeCl(3). The effects of iron concentration on adhesive properties were different for strains 241 and CDC-E8392, of the sucrose-fermenting and non-sucrose-fermenting biotypes, respectively. Iron-limited conditions enhanced interaction of strain 241 with erythrocytes and HEp-2 cells. Inhibition assays suggested the involvement of nonfimbrial protein combination 67-72p on hemagglutination of diphtheria bacilli grown under iron-limited conditions. Conversely, iron limitation inhibited adherence to glass and expression of electron-dense material on the bacterial surface. Lectin binding assays demonstrated a reduction in the number of sialic acid residues and an increase in D-mannose and D-galactose residues on the surfaces of both strains. Thus, iron exerts a regulatory role on adhesive properties of diphtheria bacilli, and low iron availability modulates the expression of C. diphtheriae surface carbohydrate moieties. The significant changes in the degree of lectin binding specific for D-mannose, D-galactose and sialic acid residues may have an effect on binding of host cells. The expression of dissimilar microbial virulence determinants may be coordinately controlled by common regulatory systems. For C. diphtheriae, the present results imply regulation of adherence and slime production as part of a global response to iron-limited environmental conditions that includes derepression of genes for the synthesis of cytotoxin and siderophores and for transport of the Fe(III)-siderophore complexes.

Bacterial Adhesion↗
PubMed1979

Interaction of diphtheria toxin with phosphorylated molecules.

The binding of diphtheria toxin to 125I-labeled cell surface glycoproteins from hamster thymocytes was shown to be inhibited by nucleotides. The relative effectiveness of the nucleotides (at 5 mM) was found to be thymidine triphosphate greater than adenosine triphosphate greater than guanosine triphosphate greater than uridine triphosphate greater than cytidine triphosphate. When adenine-containing compounds were used, the relative effectiveness was determined to be adenosine tetraphosphate greater than adenosine triphosphate greater than adenosine diphosphate greater than adenosine monophosphate. In addition, tetrapolyphosphate, tripolyphosphate, inositol hexaphosphate (phytic acid), and the highly phosphorylated proteins casein and phosvitin were also shown to be potent inhibitors of the binding of diphtheria toxin to 125I-labeled cell surface glycoproteins. Diphtheria toxin was shown to bind directly to 125I-casein; this binding was also inhibited by the highly phosphorylated compounds and was decreased by pretreatment of the 125I-casein with alkaline phosphatase. These results suggest that diphtheria toxin binds to regions of high phosphate density and raise the possibility that the site on the cell surface glycoproteins to which diphtheria toxin binds might be polyanionic in nature.

Adenine Nucleotides↗