An Isogenic Hemoglobin Receptor–Deficient Mutant of<i>Haemophilus ducreyi</i>Is Attenuated in the Human Model of Experimental Infection

Al‐Tawfiq, Jaffar A.; Fortney, Kate R.; Katz, Barry P.; Hood, Antoinette F.; Elkins, Christopher A.; Spinola, Stanley M.

doi:10.1086/315309

Cited by 80 publications

(75 citation statements)

References 37 publications

(73 reference statements)

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“…A modified escalating doseresponse study was used to compare the virulence of 35000HP-SMS2 and 35000HP (1,21,36). In the first iteration, we attempted to inoculate three subjects at three sites with EDDs of The result of the first iteration suggested that the mutant formed pustules at a rate similar to that of the parent.…”

Section: Resultsmentioning

confidence: 99%

“…H. ducreyi clumps in vitro, and it would be technically difficult to perform a mutant-parent comparison using a single dose of bacteria. Therefore, we evaluated the virulence of the mutant using a modified escalating dose-response study, as described previously (1,21,36). Within an EDD range of 17 to 120 CFU, where the parent generally forms pustules (2), the parent strain formed pustules at 70% of sites and the mutant formed pustules at 40% of sites (P ϭ 0.14).…”

Section: Discussionmentioning

confidence: 99%

“…An escalating dose response study was used to compare the parent and mutant (1,21,36). In the first iteration, three subjects were enrolled.…”

Section: Methodsmentioning

confidence: 99%

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Evaluation of an Isogenic Major Outer Membrane Protein-Deficient Mutant in the Human Model of Haemophilus ducreyi Infection

Throm

Al‐Tawfiq²,

Fortney³

et al. 2000

Infect Immun

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Evaluation of an Isogenic Major Outer Membrane Protein-Deficient Mutant in the Human Model of Haemophilus ducreyi Infection

Throm

Al‐Tawfiq²,

Fortney³

et al. 2000

Infect Immun

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“…Although the expression of HmbR in vivo has not been unambiguously confirmed, the expression of other hemoglobin receptors in vivo, such as those of certain Haemophilus species, has been reported. The in vivo expression of the outer membrane hemoglobin receptors in H. influenzae has been demonstrated in the human model for acute otitis media, and the hemoglobin receptor for Haemophilus ducreyi has been shown to be essential for infection in a human model system (6,172). A strong disadvantage associated with both HmbR and HpuAB as vaccine candidates is the phase variation of their expression and sometimes a very high frequency of switching to "off."…”

Section: Downloaded Frommentioning

confidence: 99%

Iron Transport Systems in Neisseria meningitidis

Perkins-Balding

Ratliff-Griffin

Stojiljković

2004

Microbiol Mol Biol Rev

147

146

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SUMMARY Acquisition of iron and iron complexes has long been recognized as a major determinant in the pathogenesis of Neisseria meningitidis. In this review, high-affinity iron uptake systems, which allow meningococci to utilize the human host proteins transferrin, lactoferrin, hemoglobin, and haptoglobin-hemoglobin as sources of essential iron, are described. Classic features of bacterial iron transport systems, such as regulation by the iron-responsive repressor Fur and TonB-dependent transport activity, are discussed, as well as more specific features of meningococcal iron transport. Our current understanding of how N. meningitidis acquires iron from the human host and the vaccine potentials of various components of these iron transport systems are also reviewed.

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“…The ability of H. ducreyi to obtain heme from hemoglobin is required for pustule formation. An isogenic hgbA mutant which is unable to utilize hemoglobin was unable to form pustules in a human experimental model of infection (5). As HgbA is conserved in geographically diverse isolates, we developed an IC test based on these MAbs to this protein.…”

mentioning

confidence: 99%

Development of a Rapid Immunodiagnostic Test for Haemophilus ducreyi

Patterson¹,

Olsen²,

Thomas³

et al. 2002

J Clin Microbiol

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Haemophilus ducreyi is the etiologic agent of chancroid, a sexually transmitted disease that increases the rate of transmission of human immunodeficiency virus. Chancroid ulcerations are difficult to distinguish from those produced by syphilis and herpes. Diagnosis based solely on clinical grounds is inaccurate, and culture is insensitive. Highly sensitive PCR has largely superseded culture as the preferred method of laboratory diagnosis; however, neither culture nor PCR is feasible where chancroid is endemic. We developed a rapid (15-min) diagnostic test based on monoclonal antibodies (MAbs) to the hemoglobin receptor of H. ducreyi, HgbA. This outer membrane protein is conserved in all strains of H. ducreyi tested and is required for the establishment of experimental human infection. MAbs to HgbA were generated and tested for cross-reactivity against a panel of geographically diverse strains. Three MAbs were found to be unique and noncompetitive and bound to all strains of H. ducreyi tested. Using an immunochromatography format, we evaluated the sensitivity and specificity of the test using geographically diverse strains of H. ducreyi, other Haemophilus strains, and other bacteria known to superinfect genital ulcers. All H. ducreyi strains were positive, and all other bacteria were negative, resulting in a specificity of 100%. The minimum number of CFU of H. ducreyi detected was 2 ؋ 10 6 CFU, and the minimum amount of purified HgbA protein detected was 8.5 ng. Although this level of sensitivity may not be sufficient to detect H. ducreyi in all clinical specimens, further work to increase the sensitivity could potentially make this a valuable bedside tool in areas where chancroid is endemic.Chancroid, caused by the gram-negative bacterium Haemophilus ducreyi (for reviews, see references 2, 47, and 60), is one of the sexually transmitted genital ulcer diseases. Although outbreaks are more prevalent in developing countries, sporadic outbreaks have occurred in the United States. Up to 50% of patients visiting sexually transmitted disease clinics in subSaharan Africa may have chancroid (12,23). Additionally, it is an independent risk factor for the heterosexual transmission of human immunodeficiency virus (HIV) (34; F. A. Plummer, M. A. Wainberg, P. Plourde, P. Jessamine, L. J. DCosta, I. A. Wamola, and A. R. Ronald, Letter, J. Infect. Dis. 161:810-811, 1990); therefore, the interest in chancroid has recently intensified. In the last 10 years, several laboratories have begun to define the molecular biology of this pathogen. The study of virulence factors, the body's immune response to infection, and potential vaccines for H. ducreyi have all made significant contributions to the understanding of this bacterium (3-10, 13-16, 22, 24, 26-28, 32, 33, 36, 38, 39, 46, 50, 53, 54, 59, 61, 64). With the genome sequence completed, the process of annotation will, undoubtedly, further accelerate progress on this strictly human pathogen (www.microbial-pathogenesis.org).At present, there are several laboratory methods for the d...

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An Isogenic Hemoglobin Receptor–Deficient Mutant ofHaemophilus ducreyiIs Attenuated in the Human Model of Experimental Infection

Cited by 80 publications

References 37 publications

Evaluation of an Isogenic Major Outer Membrane Protein-Deficient Mutant in the Human Model of Haemophilus ducreyi Infection

Evaluation of an Isogenic Major Outer Membrane Protein-Deficient Mutant in the Human Model of Haemophilus ducreyi Infection

Iron Transport Systems in Neisseria meningitidis

Development of a Rapid Immunodiagnostic Test for Haemophilus ducreyi

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