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PubMed1995

Swine model of Haemophilus ducreyi infection.

Haemophilus ducreyi is a strict human pathogen that causes sexually transmitted genital ulcer disease. We infected domestic swine with H. ducreyi 35000, resulting in the development of cutaneous ulcers histologically resembling human chancroid lesions. Intraepidermal lesions progressed from pustules to ulcers containing polymorphonuclear leukocytes and were accompanied by a dermal inflammatory infiltrate containing T cells and macrophages. H. ducreyi was recovered from lesions up to 17 days after inoculation, and pigs did not develop immunity to reinfection with the challenge strain. Features of the model include inoculation through abrasions in the epidermis, ambient housing temperatures for infected pigs, the ability to deliver multiple different inocula to a single host, and the availability of monoclonal antibodies against porcine immune cells permitting immunohistochemical characterization of the host immune response to H. ducreyi infection.

Animals↗
PubMed1999

Expression of sialylated or paragloboside-like lipooligosaccharides are not required for pustule formation by Haemophilus ducreyi in human volunteers.

The lipooligosaccharide (LOS) of Haemophilus ducreyi, the etiologic agent of chancroid, chemically and immunologically resembles human glycosphingolipid antigens. To test whether LOS that contains paragloboside-like structures was required for pustule formation, an isogenic mutant (35000HP-RSM2) was constructed in losB, which encodes D-glycero-D-manno-heptosyltransferase. 35000HP-RSM2 produces a truncated LOS whose major glycoform terminates in a single glucose attached to a heptose trisaccharide core and 2-keto-3-deoxyoctulosonic acid. Five human subjects were inoculated with 35000HP and 35000HP-RSM2 in a dose-response trial. For estimated delivered doses (EDDs) of >/=25 CFU, the pustule formation rates were 80% for 35000HP and 58% for 35000HP-RSM2. Preliminary data indicated that a previously described Tn916 losB mutant made a minor glycoform that does not require DD-heptose to form the terminal N-acetyllactosamine. If 35000HP-RSM2 made this glycoform, then 35000HP-RSM2 could theoretically make a sialylated glycoform. To test whether sialylated LOS was required for pustule formation, a second trial comparing an isogenic sialyltransferase mutant (35000HP-RSM203) to 35000HP was performed in five additional subjects. For EDDs of >/=25 CFU, the pustule formation rates were 30% for both 35000HP and 35000HP-RSM203. The histopathology and recovery rates of H. ducreyi from surface cultures and biopsies obtained from mutant and parent sites in both trials were similar. These results indicate that neither the expression of a major glycoform resembling paragloboside nor sialylated LOS is required for pustule formation by H. ducreyi in humans.

Adult↗
PubMed2000

Construction and characterization of Haemophilus ducreyi lipooligosaccharide (LOS) mutants defective in expression of heptosyltransferase III and beta1,4-glucosyltransferase: identification of LOS glycoforms containing lactosamine repeats.

To begin to understand the role of the lipooligosaccharide (LOS) molecule in chancroid infections, we constructed mutants defective in expression of glycosyltransferase genes. Pyocin lysis and immunoscreening was used to identify a LOS mutant of Haemophilus ducreyi 35000. This mutant, HD35000R, produced a LOS molecule that lacked the monoclonal antibody 3F11 epitope and migrated with an increased mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Structural studies indicated that the principal LOS glycoform contains lipid A, Kdo, and two of the three core heptose residues. HD35000R was transformed with a plasmid library of H. ducreyi 35000 DNA, and a clone producing the wild-type LOS was identified. Sequence analysis of the plasmid insert revealed one open reading frame (ORF) that encodes a protein with homology to the WaaQ (heptosyltransferase III) of Escherichia coli. A second ORF had homology to the LgtF (glucosyltransferase) of Neisseria meningitidis. Individual isogenic mutants lacking expression of the putative H. ducreyi heptosyltransferase III, the putative glucosyltransferase, and both glycosyltransferases were constructed and characterized. Each mutant was complemented with the representative wild-type genes in trans to restore expression of parental LOS and confirm the function of each enzyme. Matrix-assisted laser desorption ionization mass spectrometry and SDS-PAGE analysis identified several unique LOS glycoforms containing di-, tri-, and poly-N-acetyllactosamine repeats added to the terminal region of the main LOS branch synthesized by the heptosyltransferase III mutant. These novel H. ducreyi mutants provide important tools for studying the regulation of LOS assembly and biosynthesis.

Amino Sugars↗
PubMed2001

Characterization of Haemophilus ducreyi-specific T-cell lines from lesions of experimentally infected human subjects.

Haemophilus ducreyi is the etiologic agent of chancroid, a sexually transmitted genital ulcer disease that facilitates the transmission of human immunodeficiency virus. In the human model of infection, the histopathology of infected sites in part resembles a delayed-type hypersensitivity (DTH) response. In this study, T cells were isolated from skin biopsy specimens obtained from 24 subjects who were infected for 7 to 14 days. One clone and 12 lines that responded to H. ducreyi antigens were obtained from 12 of the subjects. Fluorescence-activated cell sorter analysis showed that the antigen-responsive lines and clone were predominantly CD3(+) and CD4(+). The lines and clone responded to H. ducreyi antigen in a dose-dependent manner and produced gamma interferon (IFN-gamma) alone or IFN-gamma and interleukin-10 (IL-10) but no IL-4 or IL-5 in response to H. ducreyi. Proliferation of T cells was dependent on the presence of autologous antigen-presenting cells. The lines showed little response to antigens prepared from other members of the Pasteurellaceae and responded to different fractions of H. ducreyi separated by preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis. We conclude that T cells that recognize H. ducreyi antigens are recruited to sites experimentally infected with the organism. The lack of cross-reactivity to the Pasteurellaceae and the response of the lines to different antigen fractions suggest that subjects are sensitized to H. ducreyi during the course of infection.

Antigens, Bacterial↗
PubMed2001

Characterization of Haemophilus ducreyi cdtA, cdtB, and cdtC mutants in in vitro and in vivo systems.

Haemophilus ducreyi expresses a soluble cytolethal distending toxin (CDT) that is encoded by the cdtABC gene cluster and can be detected in culture supernatant fluid by its ability to kill HeLa cells. The cdtA, cdtB, and cdtC genes of H. ducreyi were cloned independently into plasmid vectors, and their encoded proteins expressed singly or in various combinations in an Escherichia coli background. All three gene products had to be expressed in order for E. coli-derived culture supernatant fluids to demonstrate cytotoxicity for HeLa cells. Isogenic H. ducreyi cdtA and cdtB mutants were constructed and used in combination with the wild-type parent strain and a previously described H. ducreyi cdtC mutant (M. K. Stevens, J. L. Latimer, S. R. Lumbley, C. K. Ward, L. D. Cope, T. Lagergard, and E. J. Hansen, Infect. Immun. 67:3900-3908, 1999) to determine the relative contributions of the CdtA, CdtB, and CdtC proteins to CDT activity. Expression of CdtA, CdtB, and CdtC appeared necessary for H. ducreyi-derived culture supernatant fluid to exhibit cytotoxicity for HeLa cells. Whole-cell sonicates and periplasmic extracts from the cdtB and cdtC mutants had no effect on HeLa cells, whereas these same fractions from a cdtA mutant had a very modest cytotoxic effect on these same human cells. CdtA appeared to be primarily associated with the H. ducreyi cell envelope, whereas both CdtB and CdtC were present primarily in the soluble fraction from sonicated cells. Both the cdtA mutant and the cdtB mutant were found to be fully virulent in the temperature-dependent rabbit model for experimental chancroid.

Animals↗
PubMed2002

In vitro and in vivo interactions of Haemophilus ducreyi with host phagocytes.

We investigated the phagocytosis of Haemophilus ducreyi both in vitro and in vivo. Human granulocyte and monocyte phagocytosis of opsonized and nonopsonized, fluorescence-labeled H. ducreyi was assessed by flow cytometry. Both Escherichia coli and noncapsulated H. influenzae were included as controls. The maximal percentage of granulocytes taken up by H. ducreyi was 35% after 90 min. In contrast, 95% of H. influenzae bacteria were phagocytosed by granulocytes after 30 min. These results indicated that H. ducreyi phagocytosis was slow and inefficient. Bacterial opsonization by using specific antibodies increased the percentage of granulocytes phagocytosing H. ducreyi from 24 to 49%. The nonphagocytosed bacteria were completely resistant to phagocytosis even when reexposed to granulocytes, indicating that the H. ducreyi culture comprised a mixture of phenotypes. The intracellular survival of H. ducreyi in granulocytes, in monocytes/macrophages, and in a monocyte cell line (THP-1) was quantified after application of gentamicin treatment to kill extracellular bacteria. H. ducreyi survival within phagocytes was poor; approximately 11 and <0.1% of the added bacteria survived intracellularly after 2 and 20 h of incubation, respectively, while no intracellular H. influenzae bacteria were recovered after 2 h of incubation with phagocytes. The role of phagocytes in the development of skin lesions due to H. ducreyi was also studied in vivo. Mice that were depleted of granulocytes and/or monocytes and SCID mice, which lacked T and B cells, were injected intradermally with approximately 10(6) CFU of H. ducreyi. Within 4 days of inoculation, the granulocyte-depleted mice developed lesions that persisted throughout the experimental period. This result reinforces the importance of granulocytes in the early innate defense against H. ducreyi infection. In conclusion, H. ducreyi is insufficiently phagocytosed to achieve complete eradication of the bacteria. Indeed, H. ducreyi has the ability to survive intracellularly for short periods within phagocytic cells in vitro. Since granulocytes play a major role in the innate defense against H. ducreyi infection in vivo, bacterial resistance to phagocytosis probably plays a crucial role in the pathogenesis of chancroid.

Animals↗
PubMed2003

Haemophilus ducreyi requires an intact flp gene cluster for virulence in humans.

An intact Haemophilus ducreyi flp operon is essential for microcolony formation in vitro. tadA is the 9th of 15 genes in the operon and has homology to NTPases of type IV secretion systems. Fifteen human volunteers were experimentally infected with both H. ducreyi 35000HP and the tadA mutant, 35000HP.400. Papules developed at similar rates at sites inoculated with the mutant and parent, while pustules formed at 36.4% of parent sites and at 0% of mutant sites (P = 0.001). Compared to 35000HP, 35000HP.400 had only a modest but significant reduction in lesion scores in the temperature-dependent rabbit model of chancroid. These data suggest that proteins secreted by the flp locus are required for full expression of virulence by H. ducreyi in humans but have less of a role in virulence in an animal model of infection.

Adult↗
PubMed2004

Expression of the LspA1 and LspA2 proteins by Haemophilus ducreyi is required for virulence in human volunteers.

Haemophilus ducreyi colocalizes with polymorphonuclear leukocytes and macrophages and evades phagocytosis during experimental infection of human volunteers. H. ducreyi contains two genes, lspA1 and lspA2, which encode predicted proteins of 456 and 543 kDa, respectively. Compared to its wild-type parent, an lspA1 lspA2 double mutant does not inhibit phagocytosis by macrophage and myelocytic cell lines in vitro and is attenuated in an experimental rabbit model of chancroid. To test whether expression of LspA1 and LspA2 was necessary for virulence in humans, six volunteers were experimentally infected. Each volunteer was inoculated with three doses (ranging from 85 to 112 CFU) of the parent (35000HP) in one arm and three doses (ranging from 60 to 822 CFU) of the mutant (35000HP Omega 12) in the other arm. The papule formation rates were 88% (95% confidence interval [95% CI], 76.8 to 99.9%) at 18 parent sites and 72% (95% CI, 44.4 to 99.9%) at 18 mutant sites (P = 0.19). However, papules were significantly smaller at mutant sites (mean size, 24.8 mm(2)) than at parent sites (mean size, 39.1 mm(2)) 24 h after inoculation (P = 0.0002). The pustule formation rates were 44% (95% CI, 5.8 to 77.6%) at parent sites and 0% (95% CI, 0 to 39.4%) at mutant sites (P = 0.009). With the caveat that biosafety regulations preclude testing of a complemented mutant in human subjects, these results indicate that expression of LspA1 and LspA2 facilitates the ability of H. ducreyi to initiate disease and to progress to pustule formation in humans.

Adolescent↗
PubMed2005

Haemophilus ducreyi targets Src family protein tyrosine kinases to inhibit phagocytic signaling.

Haemophilus ducreyi, the etiologic agent of the sexually transmitted disease chancroid, has been shown to inhibit phagocytosis of both itself and secondary targets in vitro. Immunodepletion of LspA proteins from H. ducreyi culture supernatant fluid abolished this inhibitory effect, indicating that the LspA proteins are necessary for the inhibition of phagocytosis by H. ducreyi. Fluorescence microscopy revealed that macrophages incubated with wild-type H. ducreyi, but not with a lspA1 lspA2 mutant, were unable to complete development of the phagocytic cup around immunoglobulin G-opsonized targets. Examination of the phosphotyrosine protein profiles of these two sets of macrophages showed that those incubated with wild-type H. ducreyi had greatly reduced phosphorylation levels of proteins in the 50-to-60-kDa range. Subsequent experiments revealed reductions in the catalytic activities of both Lyn and Hck, two members of the Src family of protein tyrosine kinases that are known to be involved in the proximal signaling steps of Fcgamma receptor-mediated phagocytosis. Additional experiments confirmed reductions in the levels of both active Lyn and active Hck in three different immune cell lines, but not in HeLa cells, exposed to wild-type H. ducreyi. This is the first example of a bacterial pathogen that suppresses Src family protein tyrosine kinase activity to subvert phagocytic signaling in hostcells.

Animals↗
PubMed1990

Use of the RapID-ANA system and sodium polyanetholesulfonate disk susceptibility testing in identifying Haemophilus ducreyi.

Haemophilus ducreyi has traditionally been difficult to identify. We have utilized simple test methods to identify 19 fresh isolates obtained during a recent outbreak of chancroid in Houston and six strains of H. ducreyi from other outbreaks. Tests were performed from growth on chocolate agar after 48 h of incubation at 35 degrees C with increased humidity and CO2. All isolates exhibited typical colonial morphology and Gram stain. Isolates were catalase negative and oxidase and nitrate positive (in enriched broth). The RapID NH system failed to identify these strains because of negative reactions with alkaline phosphatase and nitrate reductase. However, by using the RapID-ANA system, all strains were positive for alkaline phosphatase and arginine, glycine, and serine aminopeptidases. Their biochemical profiles were distinct from those obtained with 66 strains representing 13 species similar to H. ducreyi. We also investigated the use of sodium polyanetholesulfonate (SPS) disk susceptibility to identify and differentiate H. ducreyi from other species. All H. ducreyi isolates were susceptible, as evidenced by the presence of a zone of inhibition with an average size of 15 mm around the SPS disk. With the exceptions of Neisseria gonorrhoeae, Gardnerella vaginalis, and Capnocytophaga spp., no other strain showed any evidence of inhibition. The latter three organisms can be easily differentiated from H. ducreyi by various features including reactions in the RapID-ANA. We conclude that, by considering simple growth and biochemical characteristics, SPS susceptibilities, and reactions in RapID-ANA, it is possible for more clinical laboratories to definitively identify this organism.

Bacteriological Techniques↗
PubMed1995

Enhanced recovery of Haemophilus ducreyi from clinical specimens by incubation at 33 versus 35 degrees C.

Isolation rates of Haemophilus ducreyi from cases of chancroid are low. Experts recommend that isolation media be incubated at 33 to 35 degrees C, but the possible effect of this temperature range on the recovery of H. ducreyi has not been evaluated. We inoculated two sets of agar plates with material from genital ulcers and incubated one set at 33 degrees C and one at 35 degrees C; incubation at 33 degrees C identified 21% more cases than did incubation at 35 degrees C (109 versus 85 cases, respectively, of the 116 cases from which an isolation was made; P < 0.01).

Agar↗
PubMed1980

Some aspects of venereal diseases in Greenland.

For many years venereal diseases have been a major problem in Greenland. Since the early 1950s gonorrhoea has been widely prevalent; in the middle of the 1960s the incidence increased rapidly. Since the early 1970s syphilis has become widespread in the population, and in 1977 an epidemic of chancroid occurred. The high figures for venereal diseases are basically due to the social change towards a modern industrial society. Improvements in the health services could be made by encouraging health education on venereal diseases, training Greenlander health personnel, and appointing a venereologist.

Adolescent↗
PubMed1981

Sexually, transmitted disease in clinic patients in Salisbury, Zimbabwe.

During the three months between December 1979 and February 1980, 2867 patients attended a sexually transmitted diseases clinic. Of the 929 (32.4%) patients examined and interviewed clinical and laboratory finding showed that chancroid was the commonest disease (38.4%) and gonorrhoea almost as common (35.3%) in men. Pelvic inflammatory disease was the commonest disease (47.0%) and gonorrhoea the next commonest (22.7%) in women.

Adult↗
PubMed1995

Asymptomatic carriage of Haemophilus ducreyi confirmed by the polymerase chain reaction.

OBJECTIVE: To investigate asymptomatic carriage of Haemophilus ducreyi by using polymerase chain reaction (PCR) on samples from women at high risk of infection. SUBJECTS: 213 commercial sex workers (CSWs) recruited in The Gambia, West Africa. METHODS: Genital samples (cervical, vaginal and ulcer) were tested for the presence of H ducreyi by PCR with the technique of "one tube nested primer". RESULTS: 12 CSWs were PCR positive for H ducreyi; 8 of these women had genital ulcers on examination. CONCLUSION: Using a simplified PCR technique for detecting H ducreyi we have shown that 2% of CSWs were carrying the organism without clinical symptoms or signs. This has important implications for sexually transmitted disease control programmes in areas with a high prevalence of chancroid.

Base Sequence↗
PubMed1996

Sexually transmitted diseases in South Africa.

AIM: To review the epidemiology of and data collection for sexually transmitted diseases (STDs) in South Africa. METHODS: Literature published since 1980 on STDs in South Africa were complied and evaluated. Historical reports and salient unpublished literature were also used in the literature review. Studies were critically reviewed in the light of sample populations and study methods, and a baseline picture of the patterns of STD burden was developed. RESULTS: The STD burden in apparently asymptomatic study populations is significant. Ulcerative infections, primarily caused by syphilis and chancroid, are present in 5-15% of asymptomatic clinic attenders; prevalence rates of gonorrhoea average 8%, with up to 13% of gonococcal isolates resistant to penicillin antibiotics. In addition, on average, chlamydia and vaginal infections are detected in 16% and 20-49%, respectively, of antenatal and family planning clinic attenders. HIV seroprevalence rates have reached 7.6% in antenatal clinic attenders. Most South African STD data are derived from ad hoc surveys which have traditionally focused only on several major infections and particular urban centres. Almost all STD studies have been facility-based, with many studies based at STD clinics, thus reporting only relative frequencies and not population-based prevalences of STDs. With the possible exception of HIV, systematic surveillance data for STDs are conspicuously lacking. CONCLUSION: The disease burden of classic sexually transmitted infections has historically been heavy, and continues to be a serious public health problem in South Africa. Morbidity from both ulcerative and non-ulcerative infections, particularly in women, is significant. The body of STD data, although mostly sound, remains incomplete, and with the rapid emergence of HIV in South Africa, surveillance of STDs and focused STD policies will be critical.

Chancroid↗
PubMed1997

STD vaccines--an overview.

OBJECTIVES: To describe the role and current status of vaccine research against sexually transmitted diseases (STDs). METHODS: The available literature was reviewed with particular emphasis on bacterial STDs. RESULTS: Strategic approaches to possible implementation of STD vaccine programmes were analysed. The status of vaccines against bacterial STDs (syphilis, chancroid, gonorrhoea, and chlamydia) is described in detail. CONCLUSIONS: The development of safe and effective STD vaccines offers a potent tool for the control of STDs, including direct and indirect prevention of HIV infection. Future priorities should be in the development of vaccines against gonorrhoea, chlamydia, and syphilis. When such vaccines become available, caution should be exercised to ensure that they do not interfere with the effectiveness of other prevention programmes.

Chancroid↗
PubMed1998

Polymerase chain reaction detection of Haemophilus ducreyi DNA.

OBJECTIVES: To develop a polymerase chain reaction (PCR) method to detect Haemophilus ducreyi DNA in cultured isolates and clinical material. METHODS: Primers specific to the H ducreyi 16s rRNA gene were synthesised. PCR conditions were optimised and products were verified by restriction endonuclease digestion and agarose gel electrophoresis. RESULTS: The method was able to detect all 28 H ducreyi strains tested; specificity was demonstrated using lysates of 12 related organisms. Applied to clinical samples from genital ulcer swabs obtained in Harare, Zimbabwe, H ducreyi DNA was detected in repeated assays in 35 clinical samples. CONCLUSION: PCR amplification using primers from the 16s rRNA gene may be a useful alternative to culture for the detection of H ducreyi and the diagnosis of chancroid.

Chancroid↗
PubMed1984

A case of mixed chancre.

A 39-year-old Norwegian seaman developed penile ulcerations after sexual contact overseas. The diagnosis of syphilitic chancre and of chancroid was confirmed. The ulcers healed after combined treatment with benzathine penicillin and trimethoprim-sulfamethoxazole.

Adult↗