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PubMed2005

Attenuated Salmonella typhimurium SL3261 as a vaccine vector for recombinant antigen in rabbits.

Oral live Salmonella vaccine vectors expressing recombinant guest antigens help stimulate systemic, mucosal, humoral, and cell-mediated immune responses against Salmonella and recombinant antigens. It may be possible to use them effectively against Haemophilus ducreyi, the bacterium that causes chancroid, a sexually transmitted genital ulcer disease. This study aimed to test the feasibility of using oral Salmonella vaccine vectors for the evaluation of chancroid vaccine candidates in the temperature-dependent rabbit model of H. ducreyi infection, an in vivo quantitative virulence assay of inducible immunity. We identified 10(8) to 10(9) CFU to be a safe and immunogenic oral dose range of S. typhimurium SL3261, by monitoring post-administration onset and course of illness and antibody titre by enzyme immunoassay (EIA). We successfully transduced plasmid pTETnir15 into the strain to produce recombinant S. typhimurium SL3261(pTETnir15), successfully expressed tetanus toxin fragment C (TetC) in it, and elicited serum anti-TetC titres of 1:6400 by EIA, 4 weeks after inoculation. The course of experimentally induced H. ducreyi skin lesions in rabbits treated with SL3261(pTETnir15) was similar to that in saline-treated controls. We describe a framework that successfully uses Salmonella as a vector for recombinant control antigen in the rabbit model of H. ducreyi infection, and is suitable for pre-clinical evaluation of Salmonella vector-based H. ducreyi vaccine antigen candidates.

Administration, Oral↗
PubMed1995

Haemophilus ducreyi: pathogenesis and protective immunity.

Haemophilus ducreyi is the etiological agent of chancroid, a sexually transmitted disease that is common in developing countries and that has characteristic genital mucocutaneous lesions. The adherence and growth of bacteria on the surface of eukaryotic cells, and the production of cytotoxin(s) result in cell damage that may be responsible for the development of ulcers. The mechanisms for protective immunity in chancroid are unclear, but both humoral and cell-mediated mechanisms may be involved.

Cells, Cultured↗
PubMed2002

Haemophilus ducreyi: clinical features, epidemiology, and prospects for disease control.

Haemophilus ducreyi is the causative agent of the genital ulcer disease chancroid. Chancroid is common in developing countries and facilitates human immunodeficiency virus transmission. In this review, the clinical features, epidemiology, and prospects for disease control are discussed in the context of experimental and natural infection of humans.

Chancroid↗
PubMed1982

Haemophilus ducreyi infections--time for reappraisal.

As the literature on Haemophilus ducreyi and clinical chancroid is reviewed, it becomes obvious that many significant findings have been forgotten over the years. As a result, from the time of Ducrey's original description of the organism in 1890 until about 1977, both clinical and laboratory experts in the United Kingdom believed that H. ducreyi infections were rare, generally acquired abroad, and almost impossible to confirm in the routine laboratory! In consequence it was a common view that it was not worth looking for H. ducreyi until all other possible causes of genital ulceration had been excluded. Moreover, the search for such an infection stopped as soon as any other cause for the patient's lesions had been found. A decision to ignore this 'rule' in Sheffield led to our looking for H. ducreyi in specimens from an unselected series of patients with genital ulceration including a number with herpes genitalis infections. The surprise finding of H. ducreyi in circumstances suggesting that it was a secondary invader made us re-examine the whole question of H. ducreyi infections and chancroid and wonder if the same organism can act as a primary pathogen and as a secondary invader. An account of the media and methods we used and of the characteristics of the organism is presented. In an attempt to find out more about the characteristic coherent colonies of H. ducreyi we studied them with the scanning electron microscope. It is clear that the whole subject of H. ducreyi infections has been neglected in the United Kingdom, but we believe that interest has now been aroused and progress will surely follow. Some areas for further investigation are suggested.

Chancroid↗
PubMed1999

Genital ulcers: etiology, clinical diagnosis, and associated human immunodeficiency virus infection in Kingston, Jamaica.

Individuals presenting consecutively with genital ulcers in Kingston, Jamaica, underwent serological testing for human immunodeficiency virus (HIV) infection, chlamydial infection, and syphilis. Ulcer material was analyzed by multiplex polymerase chain reaction (M-PCR) analysis. DNA from herpes simplex virus (HSV), Haemophilus ducreyi, and Treponema pallidum was detected in 158 (52.0%), 72 (23.7%), and 31 (10.2%) of 304 ulcer specimens. Of the 304 subjects, 67 (22%) were HIV-seropositive and 64 (21%) were T. pallidum-seroreactive. Granuloma inguinale was clinically diagnosed in nine (13.4%) of 67 ulcers negative by M-PCR analysis and in 12 (5.1%) of 237 ulcers positive by M-PCR analysis (P = .03). Lymphogranuloma venereum was clinically diagnosed in eight patients. Compared with M-PCR analysis, the sensitivity and specificity of a clinical diagnosis of syphilis, herpes, and chancroid were 67.7%, 53.8%, and 75% and 91.2%, 83.6%, and 75.4%, respectively. Reactive syphilis serology was 74% sensitive and 85% specific compared with M-PCR analysis. Reported contact with a prostitute in the preceding 3 months was associated with chancroid (P = .009), reactive syphilis serology (P = .011), and HIV infection (P = .007). The relatively poor accuracy of clinical and locally available laboratory diagnoses pleads for syndromic management of genital ulcers in Jamaica. Prevention efforts should be intensified.

Adult↗
PubMed1989

Production of monoclonal antibodies specific for Haemophilus ducreyi: a screening method to discriminate specific and cross-reacting antibodies.

Haemophilus ducreyi is the etiological agent of chancroid. The organism shares extensive immunological cross-reactivity with other Haemophilus species. This presents substantial difficulties for the production of specific monoclonal antibodies (MAbs). A competition ELISA was devised for hybridoma screening which allowed the detection of H. ducreyi-specific antibody-producing hybridoma cultures during the initial screening process. With this screening method, seven MAbs specific for H. ducreyi were obtained in a single cell fusion exercise. The specificities of the 7 MAbs were demonstrated by direct ELISA and dot immunobinding assays against several strains each of H. influenzae, H. parainfluenzae and Neisseria gonorrhoeae. Five of the MAbs reacted against all ten strains of H. ducreyi. These MAbs may permit the development of rapid and efficient immunodiagnostics for chancroid. The principle of the competition ELISA for hybridoma screening should be widely applicable to the development of specific MAbs to other organisms in which immunological cross-reactivity is an impediment to hybridoma screening by conventional methods.

Animals↗
PubMed1994

Experimental human infection with Haemophilus ducreyi.

Four subjects were experimentally infected with Haemophilus ducreyi. Lesions developed only at sites where live bacteria were inoculated on abraded skin. No subject developed fever, lymphadenopathy, or disseminated infection during a 3-day observation period. Two subjects who were rechallenged 2 months after initial infection also developed lesions. The amount of H. ducreyi recovered from 10 of 12 biopsies that were semiquantitatively cultured varied widely. Similar histologic features were present in initial and second infections. The epidermis contained pustules; the dermis contained an infiltrate of T cells and macrophages and reactive endothelial cells. Keratinocytes and T cells expressed HLA-DR, consistent with a delayed-type hypersensitivity response. The subjects did not mount humoral responses to bacterial proteins and to lipooligosaccharides after primary and secondary challenges. Thus, human experimental infection with H. ducreyi is well tolerated and safe. Recruitment of T cells and macrophages into chancroid lesions may partially explain the association between chancroid and human immunodeficiency virus transmission.

Adult↗
PubMed1995

Sexually transmitted diseases and human immunodeficiency virus control in Malawi: a field study of genital ulcer disease.

Men with genital ulcer disease (GUD) attending a clinic in Malawi were evaluated and treated with one of five drug regimens. Haemophilus ducreyi was isolated from 204 (26.2%) of 778 patients. Of 677 men, 198 (29.2%) had treponemes detected in ulcer material by direct immunofluorescence or had rapid plasma reagin reactivity of > or = 1:8. Human immunodeficiency virus type 1 (HIV-1) seroprevalence was 58.9% overall and 75.8% among patients reporting a history of GUD (P < .001). By logistic regression analysis, HIV-1 seropositivity was shown to impair ulcer healing (P = .003). Treatment failure rates for culture-proven chancroid were 19% for trimethoprim-sulfamethoxazole, 12.9% and 7.4%, respectively, for low- and high-dose erythromycin regimens, and 8.3% and 0, respectively, for low- and high-dose ciprofloxacin regimens. Herpes antigen was detected by EIA in 6 (23.1%) of 26 nonhealing ulcers. In Malawi, GUD should be managed as a syndrome to assure treatment of both syphilis and chancroid.

Chancroid↗
PubMed2005

In vitro and in vivo activity of combination antimicrobial agents on Haemophilus ducreyi.

OBJECTIVES: Development of single dose antibiotic treatments for chancroid has been followed by drug-resistant Haemophilus ducreyi in endemic areas. We examined the activity and interactions of antimicrobial agents and combinations against H. ducreyi. METHODS: We evaluated the in vitro susceptibility of three virulent strains of H. ducreyi to ceftriaxone, azithromycin, rifabutin and streptomycin, and each two-drug combination by the agar dilution method. We then tested each two-antibiotic combination for activity by the chequerboard method. Lastly, we chose the antibiotic combination with the lowest fractional inhibitory concentration index (FICI) and tested combined sub-therapeutic doses, the highest doses which had no effect alone on lesion healing compared with controls, for in vivo interaction in the temperature-dependent rabbit model of H. ducreyi infection. RESULTS: Each H. ducreyi strain was susceptible in vitro to each antibiotic and two-antibiotic combination, and combined ceftriaxone and streptomycin had the lowest FICI at 0.63. In five treated animals versus three untreated controls, combined sub-therapeutic doses of ceftriaxone (0.05 mg/kg) and streptomycin (10 mg/kg) reduced mean (SD) duration of culture positivity from 7.3 (1.1) to 2.6 (1.7) days (P<0.001), time to 50% reduction in lesion size from 9.7 (1.5) to 5.8 (0.8) days (P<0.005), and time to resolution of ulcer from 11.7 (2.3) to 6.6 (1.7) days (P<0.05). CONCLUSIONS: Ceftriaxone and streptomycin have in vivo synergic interaction against H. ducreyi lesions in the temperature-dependent rabbit model of infection. Antibiotic combinations may be evaluated clinically as single-dose therapy for chancroid.

Animals↗
PubMedDate not supplied

Problems in the treatment of bacterial sexually transmitted diseases.

Despite the development of many antimicrobial drugs that are active against sexually transmitted bacterial pathogens, various problems limit the success of treatment of bacterial sexually transmitted diseases (STD). These problems include the evolution and spread of antibiotic-resistant pathogens, inconsistent therapeutic efficacy of some regimens despite in-vitro activity against the infecting organism, toxicity, inconvenience of administration, lack of compliance by patients, and cost. Diseases affected by one or more of these therapeutic problems include gonorrhea, chlamydial infections, pelvic inflammatory disease, bacterial vaginosis, syphilis, and chancroid. Ceftriaxone, a new cephalosporin, addresses some of these problems as they relate to gonorrhea, chancroid, and, possibly, syphilis.

Anti-Bacterial Agents↗
PubMedDate not supplied

Etiology of nonvesicular genital ulcers in Winnipeg.

Twenty-eight patients with recent onset of nonvesicular ulcerative genital lesions were studied prospectively to define the microbial etiology. Causative agents identified included herpes simplex virus (HSV), Chlamydia trachomatis, Haemophilus ducreyi, and Treponema pallidum. Three women and 25 men (seven of whom were homosexual) were studied. Ten patients did not have an etiology identified. Nine patients had syphilis, six had genital herpes, one had chancroid, one had granuloma inguinale, and one had a human bite injury. Six of seven homosexual men had syphilis, as compared with one of eight heterosexual men (P less than .002). Among heterosexual men, five had atypical HSV infections, three with extensive balanoposthitis and two with chancroidal ulcers. Of the clinical characteristics examined, induration of the ulcer base and tenderness on palpation were predictive of etiology, whereas numbers of ulcers and regional lymphadenopathy were not. H. ducreyi was not a common cause of genital ulcers in Winnipeg, and it was not found as a commensal or superinfecting organism in ulcers caused by other agents.

Adolescent↗
PubMedDate not supplied

The etiology of genital ulceration in Rwanda.

The etiology of genital ulcer disease was determined in 210 consecutive patients (110 men and 100 women) who presented at a clinic in Kigali, Rwanda, because of genital ulcers. When mixed infections are included, syphilis (21%), chancroid (24%), and genital herpes (17%) were about equally frequent in men. Lymphogranuloma venereum with ulceration was found in 11% of patients. Syphilis (40%) was the most common diagnosis in women; genital herpes (20%), lymphogranuloma venereum with ulceration (19%) and chancroid (12%) also were frequent diagnoses. Microscopic examination for treponemes after silver-impregnation staining had a poor sensitivity and specificity for the diagnosis of primary syphilis. Overall, 59% of the patients (43% of the men and 77% of the women) had IgG antibodies to the human immunodeficiency virus.

Adolescent↗
PubMed2002

Men are more susceptible than women to pustule formation in the experimental model of Haemophilus ducreyi infection.

BACKGROUND: Naturally occurring chancroid is usually more prevalent in men than in women. GOAL: To examine whether there were gender differences in susceptibility to Haemophilus ducreyi infection by analyzing the papule and pustule formation rates for men and women who were experimentally inoculated with Haemophilus ducreyi. STUDY DESIGN: Ninety volunteers were included in the analysis. A total of 189 sites were available for estimation of the papule formation rate, and 166 sites for estimation of the pustule formation rates using logistic regression modeling. RESULTS: Although there were no gender differences in papule formation rates, the women had significantly lower rates of pustule formation than the men after adjustment for the estimated delivered dose. CONCLUSIONS: In women the disease will resolve and not progress to the pustular stage of disease as often as in men. The high male-to-female ratio in naturally occurring chancroid may in part reflect biological differences in gender susceptibility to disease progression, although the mechanisms responsible for this difference are unclear.

Adult↗
PubMed1987

Histological aspects of sexually transmitted genital lesions.

Occasional biopsies of genital lesions due to chancroid, secondary syphilis (the condyloma latum) and granuloma inguinale are encountered in routine histopathological practice. These lesions have specific microscopical appearances enabling a confident, or at least a presumptive, diagnosis to be made in most cases, yet the value of biopsy in the diagnosis of these diseases is not generally appreciated. The ulcer of chancroid shows three zones--a narrow superficial zone of degenerate leucocytes and fibrin, a broader middle zone with characteristic vascular changes, and a deep zone in which there is a plasma cell and lymphocyte infiltrate. The condyloma latum shows hyperplasia of the epidermis which is infiltrated with polymorphonuclear leucocytes in addition to the mononuclear infiltration of the dermis. Large numbers of spirochaetes are found in the area of the polymorph exocytosis of the epidermis. The inflammatory infiltrate of granuloma inguinale consists of a neutrophil and plasma cell infiltrate with moderate numbers of large mononuclear cells in which there are one or more vacuoles containing Donovan bodies.

Biopsy↗
PubMed1992

Correlation between in vitro antimicrobial susceptibilities and beta-lactamase plasmid contents of isolates of Haemophilus ducreyi from the United States.

We determined the susceptibilities of 94 strains of Haemophilus ducreyi isolated in various municipalities in the United States between 1982 and 1989 to the following antimicrobial agents: amoxicillin-clavulanic acid, ceftriaxone, erythromycin, azithromycin, ciprofloxacin, ofloxacin, trimethoprim, and spectinomycin. Ceftriaxone (MIC, less than or equal to 0.008 micrograms/ml), azithromycin (MIC, less than or equal to 0.125 micrograms/ml), erythromycin (MIC, less than or equal to 0.125 micrograms/ml), ciprofloxacin (MIC, less than or equal to 0.25 micrograms/ml), and ofloxacin (MIC, less than or equal to 0.25 micrograms/ml) were highly active against all isolates. Amoxicillin-clavulanic acid (MICs, 0.25 to 8.0 micrograms/ml), trimethoprim (MICs, 0.06 to 16.0 micrograms/ml), and spectinomycin (MICs, 2.0 to greater than or equal to 32.0 micrograms/ml) were less active against these isolates. Isolates possessing the 5.7-MDa beta-lactamase plasmid were less susceptible to erythromycin, trimethoprim, and spectinomycin than were isolates possessing the 3.2-MDa beta-lactamase plasmid. The susceptibilities of plasmidless isolates to erythromycin, trimethoprim, and spectinomycin were distributed bimodally; the median MIC for the more susceptible plasmidless isolates corresponded to that for isolates with the 3.2-MDa plasmid, and the median MIC for the less susceptible plasmidless isolates corresponded to that for isolates with the 5.7-MDa plasmid. Thus, plasmid profiles may be valuable markers for geographical variations in antimicrobial susceptibilities of H. ducreyi strains that may indicate the relative efficacy of regimens for the treatment of chancroid. Of the regimens recommended by the U.S. Public Health Service for the treatment of chancroid, our results support the use of erythromycin, ceftriaxone, and ciprofloxacin, and perhaps ofloxacin, but suggest that amoxicillin-clavulanic acid and sulfamethoxazole-trimethoprim should be used with caution.

Anti-Bacterial Agents↗
PubMed1995

Use of tissue culture and animal models to identify virulence-associated traits of Haemophilus ducreyi.

To identify virulence-associated properties of Haemophilus ducreyi, 34 strains of this sexually transmitted pathogen were evaluated for in vitro phenotypic characteristics of potential relevance to chancroid pathogenesis and for their ability to produce lesions in the temperature-dependent animal model for chancroid. Of the 34 strains tested, all but three produced a cytopathic effect on human foreskin fibroblasts (HFF) and all but six strains formed large microcolonies on HFF monolayers. A subset of 12 selected strains underwent more extensive analyses and, when evaluated for both their cytadherence kinetics and growth in the presence of HFF monolayers, it was found that several of these strains had a very limited ability to attach to HFF cells. When the same 12 strains were tested in the temperature-dependent rabbit model, only the seven strains which were positive in all of these in vitro-based tests readily produced lesions. In contrast, the five strains that were noted to be deficient in one or more of the phenotypic characteristics scored in the in vitro systems did not produce lesions. This association between the traits measured in vitro and the ability to produce dermal lesions was significant (P = 0.0012). These results suggest that in vitro behavior may be used to predict the virulence potential of H. ducreyi strains. Moreover, the phenotypic characteristics described in this study are appropriate focal points for efforts to determine the molecular basis of the virulence of this pathogen.

Animals↗
PubMed1996

The conserved 18,000-molecular-weight outer membrane protein of Haemophilus ducreyi has homology to PAL.

Haemophilus ducreyi expresses an 18,000-molecular-weight outer membrane protein that contains a conserved surface-exposed epitope recognized by monoclonal antibody 3B9. Monoclonal antibody 3B9 cross-reacts with proteins of similar molecular weight found in many Haemophilus sp. strains, including P6, a candidate vaccine for Haemophilus influenzae. The gene encoding the 18,000-molecular-weight outer membrane protein was identified by screening a lambdagt11 genomic library with 3B9. The coding sequence of the gene was localized to a 471-bp open reading frame, designated pal (peptidoglycan-associated lipoprotein). Translation of pal predicted a mature polypeptide with a molecular weight of 15,000 that had extensive homology with P6 and Escherichia coli PAL. The predicted signal peptide had features characteristic of a prokaryotic lipoprotein, and processing of PAL was sensitive to globomycin in H. ducreyi. The sequences encoding mature H. ducreyi PAL were subcloned into the vector pRSET B and expressed as a polyhistidine-containing fusion protein that bound 3B9. In Western blot (immunoblot) analysis, serum samples obtained from healthy subjects and patients with chancroid or other genital ulcer diseases contained antibodies to purified PAL. Antibodies that bound to PAL were removed by absorption with a lysate of Haemophilus sp. antigens, suggesting that patients with chancroid do not develop an H. ducreyi-specific antibody response to PAL.

Amino Acid Sequence↗
PubMed1999

Examination of early interactions between Haemophilus ducreyi and host cells by using cocultured HaCaT keratinocytes and foreskin fibroblasts.

Haemophilus ducreyi is the etiologic agent of chancroid, a sexually transmitted genital ulcer disease. Keratinocytes are likely the first cell type encountered by H. ducreyi upon infection of human skin; thus, the interaction between H. ducreyi and keratinocytes is probably important for the ability of H. ducreyi to establish infection. We have used the HaCaT keratinocyte cell line grown in monolayers and in cocultures with HS27 fibroblasts to investigate H. ducreyi interactions with keratinocytes and the host-cell response to H. ducreyi infection. Using quantitative adherence and gentamicin protection assays, we determined that approximately 13% of H. ducreyi adhered to HaCaT cell monolayers, while only a small proportion (0.0052%) was intracellular. By transmission electron microscopy, we observed numerous H. ducreyi organisms adherent to but rarely within HaCaT cells cocultured with fibroblasts. Both live H. ducreyi and purified H. ducreyi lipooligosaccharide (LOS) induced significant interleukin 8 (IL-8) expression from HaCaT cell-HS27 cell cocultures. However, the level of IL-8 expression in response to LOS alone was not as pronounced. H. ducreyi LOS was a more potent inducer of IL-8 from cocultures than Escherichia coli lipopolysaccharide (LPS) at the same concentration, suggesting a unique effect of H. ducreyi LOS on cocultures. Neither live H. ducreyi nor purified H. ducreyi LOS or E. coli LPS induced tumor necrosis factor alpha expression from cocultures. H. ducreyi induced drastically different cytokine profiles from cocultures than from HS27 or HaCaT cells cultured separately. IL-8 expression by skin cells in response to H. ducreyi infection in vivo may be responsible for the massive influx of polymorphonuclear leukocytes and other inflammatory cells to the site of infection. This influx of inflammatory cells may be partly responsible for the tissue destruction characteristic of chancroid.

Bacterial Adhesion↗