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PubMed1997

In vitro expression of the diphtheria toxin A-chain gene under the control of human chorionic gonadotropin gene promoters as a means of directing toxicity to ovarian cancer cell lines.

OBJECTIVE: Our goal was to determine whether toxicity of the diphtheria toxin A-chain gene regulated by the human chorionic gonadotropin promoter can be directed to malignant ovarian cell lines. STUDY DESIGN: Plasmids containing diphtheria toxin A-chain gene linked to the regulatory elements of the metalloergothioneine and human chorionic gonadotropin promoters were transfected into the cell lines. Expression of diphtheria toxin A-chain gene was determined by the inhibition of a cotransfected luciferase reporter gene. RESULTS: Cytotoxicity of the diphtheria toxin A-chain gene is shown in a dose-responsive manner. Transfection of a plasmid expressing the diphtheria toxin A-chain gene controlled by a constitutive promoter readily inhibits protein synthesis. Specific inhibition of luciferase protein synthesis occurs in ovarian cancer cells transfected with the diphtheria toxin A-chain gene under the control of the human chorionic gonadotropin promoters when compared with normal ovarian epithelial cells or fibroblasts. CONCLUSIONS: These data demonstrate the preferential expression of the diphtheria toxin A-chain gene, regulated by the human chorionic gonadotropin promoter, to ovarian cancer cell lines. This provides an avenue for targeting such cells for suicide, toxin, or cytokine genes.

Carcinoma↗
PubMed1999

Epidemiology of epidemic diphtheria in three regions, Russia, 1994-1996.

BACKGROUND: A massive diphtheria epidemic which began in the former Soviet Union in 1990 is the first large-scale diphtheria epidemic in developed countries in more than 30 years and has primarily affected adults. In response, health authorities attempted to maximize vaccination for children and conducted an unprecedented campaign to vaccinate adults. METHODS: We analyzed diphtheria surveillance data (case report forms and diphtheria vaccine coverage data) from three Russian regions from January 1994 to December 1996 and estimated vaccine effectiveness by the screening method. RESULTS: We reviewed records from 2243 (97.2%) of 2307 reported cases. The highest cumulative incidence in the period was among children aged 5 to 9 years (106 cases per 100,000 population); adults aged 40-49 years had the highest adult incidence for disease (88 cases per 100,000) and the highest incidence of any age group of clinically severe disease (29 cases per 100,000) and death (5.1 deaths per 100,000). The incidence among women aged 2049 years (82 per 100,000 women) was higher than among men (47 per 100,000, p<0.01). The annual incidence decreased from 25.2 cases per 100,000 population in 1994 to 9.4 cases per 100,000 in 1996. The decrease occurred as adult coverage increased from an estimated 25-30% in December 1992 to 88% in December 1995. Vaccine effectiveness was high among both children and adults. CONCLUSIONS: The Russian diphtheria epidemic primarily affected adults, especially women; this pattern is likely representative of diphtheria epidemics in immunized populations. Raising childhood immunization coverage and mass adult vaccination was effective in controlling the Russian epidemic. An improved understanding of the current epidemiology of diphtheria will be useful to design public health responses to prevent or control modern epidemics.

Adolescent↗
PubMed1976

A diphtheria outbreak in Dade County, Florida.

During a 16-week period in late 1969, 11 cases of diphtheria (three fatal) were reported from Miami, Dade County, Florida. For each of ten previous years, two cases at most had been reported. All patients resided in a predominantly black, low socioeconomic community within the 7-square-mile Model City area. Nine patients had positive cultures for toxigenic Corynebacterium diphtheriae, mitis strain. None of the 11 patients or 22 culture-positive household contacts had been vaccinated against diphtheria. During the outbreak, one dose of diphtheria-tetanus-pertussis vaccine or tetanus-diphtheria toxoid was given to more than 90,000 residents of Model City (95%) and to more than 200,000 residents of Dade County (16%). A state law was passed in June 1971 requiring all children to be vaccinated before entering school. No subsequent cases of diphtheria were reported in the ensuing five-year period. The Miami experience suggests that prompt mass vaccination will abort the spread of epidemic diphtheria and emphasizes the need for routine vaccination to minimize morbidity and mortality.

Adolescent↗
PubMed1968

Tissue culture method for toxigenicity testing of Corynebacterium diphtheriae.

A method for toxigenicity testing of Corynebacterium diphtheriae in tissue cultures was developed. Results were obtained by comparing destruction of the monkey kidney or, preferably, rabbit kidney monolayer by 0.1 ml of the C. diphtheriae culture in Elek's broth containing 20% rabbit serum with the appearance after the addition of 0.2 ml of a mixture of the C. diphtheriae culture and diphtheria antitoxin. The mixture of C. diphtheriae broth culture and 10 antitoxin units per ml was incubated for 1 hr at room temperature before it was added to the tissue cultures which were then incubated as long as 5 days; most results, however, were read in 72 hr. Elek's broth medium was superior to heart infusion broth for toxin production by C. diphtheriae. Addition of 20% rabbit serum improved toxin production in either broth. Numerous toxigenic and atoxigenic C. diphtheriae cultures were tested for toxigenicity in primary rabbit and monkey kidney tissue cultures. If properly controlled, this in vitro method appeared to have an advantage over the in vitro agar gel method; its results were comparable with the rabbit intradermal test. With the wider use of tissue cultures in most laboratories, we believe that the tissue culture method for toxigenicity would be more economical and easier to perform than the animal intradermal method.

Animals↗
PubMed1999

Identification of a two-component signal transduction system from Corynebacterium diphtheriae that activates gene expression in response to the presence of heme and hemoglobin.

Corynebacterium diphtheriae, the causative agent of diphtheria, utilizes various host compounds to acquire iron. The C. diphtheriae hmuO gene encodes a heme oxygenase that is involved in the utilization of heme and hemoglobin as iron sources. Transcription of the hmuO gene in C. diphtheriae is controlled under a dual regulatory mechanism in which the diphtheria toxin repressor protein (DtxR) and iron repress expression while either heme or hemoglobin is needed to activate transcription. In this study, two clones isolated from a C. diphtheriae chromosomal library were shown to activate transcription from the hmuO promoter in Escherichia coli. Sequence analysis revealed that these activator clones each carried distinct genes whose products had significant homology to response regulators of two-component signal transduction systems. Located upstream from each of these response regulator homologs are partial open reading frames that are predicted to encode the C-terminal portions of sensor kinases. The full-length sensor kinase gene for each of these systems was cloned from the C. diphtheriae chromosome, and constructs each carrying one complete sensor kinase gene and its cognate response regulator were constructed. One of these constructs, pTSB20, which carried the response regulator (chrA) and its cognate sensor kinase (chrS), was shown to strongly activate transcription from the hmuO promoter in a heme-dependent manner in E. coli. A mutation in chrA (chrAD50N), which changed a conserved aspartic acid residue at position 50, the presumed site of phosphorylation by ChrS, to an asparagine, abolished heme-dependent activation. These findings suggest that the sensor kinase ChrS is involved in the detection of heme and the transduction of this signal, via a phosphotransfer mechanism, to the response regulator ChrA, which then activates transcription of the hmuO promoter. This is the first report of a bacterial two-component signal transduction system that controls gene expression through a heme-responsive mechanism.

Alleles↗
PubMed2005

The first case of septicemia due to nontoxigenic Corynebacterium diphtheriae in Poland: case report.

BACKGROUND: Toxigenic strains of Corynebacterium diphtheriae are well known agent of diphtheria. Nontoxigenic strains can cause atypical course of the disease. Invasive diseases caused by C. diphtheriae occur very rare. CASE PRESENTATION: We have described the first case of septicemia and endocarditis due to nontoxigenic C. diphtheriae biotype gravis in Poland. The patient has not belonged to any group of risk such infection. CONCLUSION: The case presented in this article shows unusual case of infection connected with nontoxigenic C. diphtheriae that took place in the area where have been no cases of diphtheria and other C. diphtheriae infections for near ten years. It shows the importance of identifying Corynebacterium isolates at the species level especially when the strain has been isolated from normally sterile sites.

Adult↗
PubMed1999

Endocytic mechanisms responsible for uptake of GPI-linked diphtheria toxin receptor.

We have here used diphtheria toxin as a tool to investigate the type of endocytosis used by a glycosylphosphatidylinositol-linked molecule, a glycosylphosphatidylinositol-linked version of the diphtheria toxin receptor that is able to mediate intoxication. The receptor is expressed in HeLa cells where clathrin-dependent endocytosis can be blocked by overexpression of mutant dynamin. Diphtheria toxin intoxicates cells by first binding to cell-surface receptors, then the toxin is endocytosed, and upon exposure to low endosomal pH, the toxin enters the cytosol where it inhibits protein synthesis. Inhibition of protein synthesis by the toxin can therefore be used to probe the entry of the glycosylphosphatidylinositol-linked receptor into an acidic compartment. Furthermore, degradation of the toxin can be used as an indicator of entry into the endosomal/lysosomal compartment. The data show that although expression of mutant dynamin inhibits intoxication mediated via the wild-type receptors, mutant dynamin does not affect intoxication or endocytosis and degradation of diphtheria toxin bound to the glycosylphosphatidylinositol-linked receptor. Confocal microscopy demonstrated that diphtheria toxin is transported to vesicles containing EEA1, a marker for early endosomes. Biochemical and ultrastructural studies of the HeLa cells used reveal that they have very low levels of caveolin-1 and that they contain very few if any caveolae at the cell surface. Furthermore, the endocytic uptake of diphtheria toxin bound to the glycosylphosphatidylinositol-linked receptor was not reduced by methyl-beta-cyclodextrin or by nystatin which both disrupt caveolar structure and functions. Thus, uptake of a glycosylphosphatidylinositol-linked protein, in this case the diphtheria toxin receptor, into the endosomal/lysosomal system can occur independently of both caveolae and clathrin-coated vesicles.

Adolescent↗
PubMed2006

Economic analysis of prevaccination serotesting compared with presumptive immunization for polio, diphtheria, and tetanus in internationally adopted and immigrant infants.

BACKGROUND: No consensus exists about whether to conduct prevaccination serotesting or to presumptively vaccinate internationally adopted and immigrant infants with inactivated polio (IPV) and diphtheria-tetanus-acellular pertussis (DTaP) immunizations. OBJECTIVE: To study the clinical and economic outcomes from a societal perspective of prevaccination serotesting in a hypothetical 12-month-old internationally adopted or immigrant infant. DESIGN AND METHODS: A decision analysis model was developed comparing presumptive vaccination with IPV versus serotesting for poliovirus type 1, 2, and 3 antibodies followed by vaccination in unprotected patients. A similar decision analysis model was developed comparing presumptive vaccination with DTaP versus serotesting for diphtheria and tetanus toxoid antibodies. The main outcome measures were cost per patient protected from polio, diphtheria, and tetanus. RESULTS: Compared with presumptive immunization, prevaccination serotesting for polio increases the cost per patient from $57 to $62 and decreases the percentage of patients protected against polio from 95.3% to 94.0%. Serotesting for diphtheria and tetanus increases the cost per patient from $62 to $119 and increases the percentage of patients protected against both diphtheria and tetanus from 91.5% to 92.3%. Presumptive immunization with DTaP costs less and is more clinically effective than serotesting if >80% of patients do not complete the full vaccine series or if antibody seroprevalence to both diphtheria and tetanus is <51%. CONCLUSIONS: Presumptive immunization for polio improves outcomes and saves costs compared with prevaccination serotesting in internationally adopted and immigrant infants. The results for DTaP are less definitive, although immunization is the preferred strategy in populations with poor vaccine compliance or low seroprevalence of antibodies to diphtheria and tetanus.

Adoption↗
PubMed1996

[Isolation of Corynebacterium diphtheriae subsp. belfanti from a cow with chronic active dermatitis].

Diphtheria is an acute communicable disease of man caused by C. diphtheriae. Pharyngeal and cutaneous forms are described, where from both toxigenic and nontoxigenic strains can be isolated. The occurrence of C. diphtheriae in dairy cattle has already been reported in the past. The pathogens were isolated from ulcerated teats and from the milk of cows with mastitis as well. These animals were considered to play a role in the transmission of the disease to man. This paper describes the isolation and characterization of C. diphtheriae in a 4 years old cow with generalized, partly ulcerative and purulent skin lesions. Bacteriological examination revealed the presence of very numerous corynebacterium-like organisms, which were characterized as C. diphtheriae subsp. belfanti, a nontoxigenic subspecies of C. diphtheriae. The significance of C. diphtheriae in veterinary medicine and the possible role of cattle as a reservoir of these organisms are discussed.

Animals↗
PubMed2000

Comparison of four serological methods for the detection of diphtheria anti-toxin antibody.

The aim of this study was to compare four serological methods for the detection of Corynebacterium diphtheriae IgG anti-toxin antibodies (IgG-DTAb) in human serum. One hundred serum samples were evaluated for C. diphtheriae IgG-DTAb by four different methods: passive haemagglutination (PHA), latex agglutination test (LA), toxoid enzyme-linked immunosorbent assay (Toxoid-ELISA), and toxin-binding inhibition enzyme-linked immunosorbent assay (ToBI-ELISA). As the external standardisation the neutralisation test for C. diphtheriae toxin in Vero cells (TN Vero) was used. For internal standardisation of IgG-DTAb titres, the WHO standard serum of human diphtheria antitoxin was used. The study revealed a poor correlation between the reference test and the PHA (r=0.34 Pearson's correlation coefficient), an acceptable correlation for the LA (r=0.74), a good correlation for the Toxoid-ELISA (r=0.81) and a very good correlation for ToBI-ELISA (r=0.93). The sensitivity measurements of PHA, LA, Toxoid-ELISA and ToBI-ELISA tests, were 14, 100, 94, 96% respectively and the corresponding specificity characteristics were 86, 76, 94, 90 respectively. Of the four evaluated methods, the ToBI-ELISA could be recommended for scientific and precise laboratory assays of diphtheria antibody levels in humans. For screening purposes the Toxoid-ELISA could be used, but the accuracy of antibody titres below 0.1 IU/ml, considered as the limits of protection, is questionable. Both tests offer very useful alternatives to the in vitro diphtheria toxin neutralisation test in Vero cells. Because of their unsatisfactory correlation and sensitivity as compared to the reference method, PHA and LA should be avoided and replaced by one of the two enzyme immunoassays.

Animals↗
PubMed1989

Diphtheria in Stockholm, with a theory concerning transmission.

Since 1984, diphtheria has been diagnosed in Sweden, mainly among men abusing alcohol. During the first half of 1986, eight cases of diphtheria were discovered in the city of Stockholm. The first three were among men abusing alcohol. The following five cases had no connection with them. These five persons were employed in two companies housed in the same building. The only connection between them was that they ate their lunch at the same restaurant. One alcohol-abusing man had worked temporarily in the kitchen of this restaurant during the week before the five cases of diphtheria arose. He knew one of the first three patients well. A throat swab taken from him a month after the five cases had been diagnosed was negative. It was suspected however, that this man might have been a carrier of Corynebacterium diphtheriae during the week that he worked in the kitchen. Tests for C. diphtheriae antitoxin revealed that the kitchen staff had high antitoxin titres although they lacked a history of basic immunisation. Even so, C. diphtheriae could not be isolated from their throats and it has not been possible to establish the mode of transmission. The most reasonable theory of transmission is that the organism was introduced into the kitchen by the man employed there temporarily and that it was spread by food served in the restaurant. This theory has not been proved but is discussed in order to facilitate future investigations of a similar outbreak.

Adult↗
PubMed1998

Factors influencing immunity against diphtheria in adults.

In about 50% of all adult Germans, serological immunity to diphtheria is lacking even though a vaccination history exists in most cases. In this study, the factors contributing to diphtheria immunity, up to 43 years after the last diphtheria vaccination, were analysed. Serum samples were taken from 287 adults whose complete vaccination history was available, and who had received a standard primary vaccination. The sera were tested by tissue culture neutralization assay for diphtheria antitoxin levels. The time lapse since the last diphtheria vaccination proved to be the most important factor influencing the protection rate. Secondly, the factor last vaccination within the first 3 years of life and, finally, female gender were found to correlate significantly with a low protection rate. No direct effect could be established for age, number of previous vaccinations, occupational contact with patients or travel within any endemic region during the last 10 years. Since diphtheritic infection can occur among previously vaccinated persons, the immunity gap observed among adults should be closed by regular diphtheria boosters. Special attention should be paid to the three groups mentioned. Further investigation is required to determine whether or not a single booster vaccination is sufficient to provide long-term protection for those in the risk groups indicated above.

Adolescent↗
PubMed2000

A randomised controlled trial with a diphtheria-tetanus-acellular pertussis (dTpa) vaccine in adults.

The aim of this assessor-blinded trial was to compare the immunogenicity and reactogenicity of a candidate diphtheria, tetanus toxoids and acellular pertussis vaccine with reduced antigen content for diphtheria and pertussis (dTpa) with a licensed reduced adult-type diphtheria-tetanus vaccine Td (reduced diphtheria content) and with an experimental candidate monovalent acellular pertussis vaccine with reduced antigen content (pa). The dTpa and pa vaccines had identical pertussis antigen content. A total of 299 healthy adults (> or =18 years, mean age: 30.1 years+/-10.7) were randomised into 3 groups to receive a single dose of one of the study vaccines. In all groups, clinically significant reactions (severe) were infrequent (0-6%) and no serious adverse events were reported during the study. The incidence of local and systemic reactions following the administration of dTpa was comparable to the Td vaccine group. Of the total study group, prior to vaccination 52. 3 and 93.2% of the subjects had anti-diphtheria and anti-tetanus antibody levels > or = 0.1 IU/ml, respectively; and 73.1, 98.2 and 74.5% of the subjects were seropositive for pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN) antibodies, respectively. One month after vaccination, a similar percentage of subjects in the dTpa and Td groups had anti-diphtheria (88.4% vs 90. 1%) and anti-tetanus (100% vs 98.9%) antibody levels > or =0.1 IU/ml. Similar anti-FHA (100%) and anti-PRN (98.9%) vaccine response rates were seen in the dTpa and pa groups, while the anti-PT vaccine response rates were 96.8 and 100.0%, respectively. The dTpa vaccine is as well tolerated and immunogenic as the licensed Td vaccine, and additionally, can also boost antibodies against pertussis.

Adhesins, Bacterial↗
PubMed1998

Diphtheria antitoxin levels in the 14-30-year age group in Italy.

In order to verify diphtheria immunity a seroepidemiological survey was performed in 1996-1997. Serum samples were obtained from 501 subjects 14 years old, recruited at 8 schools in Rome, and from 490 subjects 20-30 years old recruited from 15 Italian regions. Serum diphtheria antitoxin was titrated using the Vero cell assay. The minimum protection level of antitoxin was set at 0.01 IU ml-1. The results show that the younger population have a good immunity to diphtheria while a large proportion of young adults is devoid of protective levels of diphtheria antitoxin. Out of the 501 subjects 14 years old, 495 (98.8%) had a diphtheria antitoxin titre > or = 0.01 IU ml(-1). Only 6 (1.2%) teenagers were susceptible. Out of the 490 subjects 20-30 years old, 109 (22.2%) were susceptible, 381 (77.8%) had a diphtheria antitoxin titre > or = 0.01 IU ml(-1). The data stress for booster immunization at the end of junior high school.

Adolescent↗
PubMed1986

[Phage lysis typing and epidemiology of diphtheria 1975-1984].

Phage typing of the available diphtheria strains from epidemics and isolated diphtheria infections in the Federal Republic of Germany since 1975 showed that the various waves of the disease were caused by pathogenic strains which differed from each other in lysis type and lysogenetic spectrum. The individual regional outbreaks, therefore, were not epidemiologically interlinked. Both a high incidence of diphtheria cases and isolated cases occurring in a particular region and within the same time period, however, were caused by the same pathogen with identical lysis type and lysogenetic pattern. On the other hand, the toxinogenic strains introduced from countries with a high prevalence of the disease had clearly different typing characteristics. According to our present studies on the incidence of pathogen carriers, no toxin-producing diphtheria bacteria are circulating in the indigenous population. It can be assumed, therefore, that the outbreaks of diphtheria during the last few years were caused by such imported strains. Since the importation of toxin-producing diphtheria bacteria is unavoidable and may occur at all times, universal active immunisation in childhood, as well as timely revaccination of adolescents and adults, are mandatory prophylactic measures to prevent new epidemics.

Bacteriophage Typing↗
PubMed2000

Epidemic diphtheria in the 1990s: Azerbaijan.

The diphtheria epidemic in the former Soviet Union reached Azerbaijan in 1991, when 66 cases of diphtheria were reported, a number that compared with 4 cases in 1990. From 1990-1996, 2182 cases of diphtheria and 286 diphtheria fatalities (case fatality rate: 13.1%) were reported in Azerbaijan, primarily among persons 5-39 years of age. Almost 45% of cases and 61% of deaths occurred among children 5-14 years of age. The high burden of severe disease among children and young adults suggested a different pattern of preexisting immunity against diphtheria in the Azerbaijani population than was observed in the concurrent diphtheria epidemic in Russia. Because resources were limited in Azerbaijan, mass immunization of the population was carried out in stages, focusing initially on school-aged children. Mass immunization campaigns targeting children were moderately successful in stabilizing the epidemic; mass immunization campaigns targeting both adults and children were eventually needed to fully stop the epidemic.

Adolescent↗
PubMed2000

Current approaches to the laboratory diagnosis of diphtheria.

Despite the success of mass immunization in many countries, diphtheria continues to play a major role as a potentially lethal resurgent infectious disease. Early, accurate diagnosis is imperative since delay in specific therapy may result in death. The microbiologic diagnosis of the disease, the identification of contacts and carriers, and the appropriate clinical management of these patients are therefore crucial. The epidemiology of diseases caused by Corynebacterium diphtheriae has changed dramatically over the decades, a situation that is highlighted by the resurgence of infections in the European region. These factors have strengthened the need for laboratories to screen for C. diphtheriae. Many modified and new methodologies are now used widely within laboratories for diphtheria diagnosis. Recent developments have focused upon methods for detection of the lethal and potent exotoxin produced by the causative organism, C. diphtheriae; this detection is the definitive test for the microbiologic diagnosis of diphtheria.

Bacteriological Techniques↗
PubMed1981

Circulating antitoxin in rabbits after ingestion of diphtheria toxoid.

Immune responses following antigen ingestion vary from stimulation to suppression depending on animal species, antigen, and experimental protocol. Young adult rabbits were given either 0.02% diphtheria toxoid or 0.1% bovine serum albumin in drinking water for 10-day periods, a protocol previously found to immunize human infants fed bovine serum albumin. Specific serum antibody was detected by radioimmunoassay in 10 of 13 rabbits fed diphtheria toxoid for 10 days and 11 of 13 rabbits fed bovine serum albumin. Response to oral diphtheria toxoid in some animals was equal to that after an injection of alum-precipitated diphtheria and tetanus toxoids. All rabbits fed a second course of either antigen showed an enhanced, rapid rise in antibody concentration. Avidity of the antibody also increased markedly, suggesting that priming and memory had been established during the first feeding. Similar anamnestic responses occurred in animals given a parenteral challenge after ingesting antigen. One month after administration of diphtheria toxoid, no significant difference in serum antibody levels was present between unfed animals challenged with diphtheria-tetanus toxoids and although avidity of the antitoxin was higher in fed animals. Antibody activity could be detected only in the immunoglobulin G serum fractions with either antigen. These responses suggest that oral immunization protocols using protein antigens can be adapted for use against toxins causing disease.

Administration, Oral↗