DsrA-Deficient Mutant of
            <i>Haemophilus ducreyi</i>
            Is Impaired in Its Ability To Infect Human Volunteers

Bong, Cliffton T. H.; Throm, Robert E.; Fortney, Kate R.; Katz, Barry P.; Hood, Antoinette F.; Elkins, Christopher A.; Spinola, Stanley M.

doi:10.1128/iai.69.3.1488-1491.2001

Cited by 66 publications

(62 citation statements)

References 42 publications

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“…However, subsequent testing in the human challenge model for experimental chancroid (for a review, see reference 31) revealed that only a few of these gene products are truly essential for full virulence of H. ducreyi. Mutations in pal (21), hgbA (1), dsrA (8), the flp gene cluster (55), ncaA (22), and lspA1 and lspA2 (29) attenuated the virulence of H. ducreyi in human volunteers, whereas mutations in four other genes caused partial attenuation (4,6,28,34).…”

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Characterization of the CpxRA Regulon in Haemophilus ducreyi

Labandeira-Rey¹,

Brautigam

Hansen³

2010

Infect Immun

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The Haemophilus ducreyi 35000HP genome encodes a homolog of the CpxRA two-component cell envelope stress response system originally characterized in Escherichia coli. CpxR, the cytoplasmic response regulator, was shown previously to be involved in repression of the expression of the lspB-lspA2 operon (M. LabandeiraRey, J. R. Mock, and E. J. Hansen, Infect. Immun. 77:3402-3411, 2009). In the present study, the H. ducreyi CpxR and CpxA proteins were shown to closely resemble those of other well-studied bacterial species. A cpxA deletion mutant and a CpxR-overexpressing strain were used to explore the extent of the CpxRA regulon. DNA microarray and real-time reverse transcriptase (RT) PCR analyses indicated several potential regulatory targets for the H. ducreyi CpxRA two-component regulatory system. Electrophoretic mobility shift assays (EMSAs) were used to prove that H. ducreyi CpxR interacted with the promoter regions of genes encoding both known and putative virulence factors of H. ducreyi, including the lspB-lspA2 operon, the flp operon, and dsrA. Interestingly, the use of EMSAs also indicated that H. ducreyi CpxR did not bind to the promoter regions of several genes predicted to encode factors involved in the cell envelope stress response. Taken together, these data suggest that the CpxRA system in H. ducreyi, in contrast to that in E. coli, may be involved primarily in controlling expression of genes not involved in the cell envelope stress response.

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confidence: 99%

Characterization of the CpxRA Regulon in Haemophilus ducreyi

Labandeira-Rey¹,

Brautigam

Hansen³

2010

Infect Immun

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“…B-451, p. 233, 1996), a copper-zinc superoxide dismutase (42), and a very large protein detected in H. ducreyi culture supernatant fluid (54). To date, isogenic mutants lacking expression of the peptidoglycan-associated lipoprotein (19), the hemoglobin-binding outer membrane protein HgbA (7), and the DsrA outer membrane protein (11) have been shown to exhibit reduced virulence in the human challenge model for experimental chancroid.…”

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Haemophilus ducreyi Requires the flp Gene Cluster for Microcolony Formation In Vitro

et al. 2002

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Haemophilus ducreyi, the etiologic agent of chancroid, has been shown to form microcolonies when cultured in the presence of human foreskin fibroblasts. We identified a 15-gene cluster in H. ducreyi that encoded predicted protein products with significant homology to those encoded by the tad (for tight adhesion) locus in Actinobacillus actinomycetemcomitans that is involved in the production of fimbriae by this periodontal pathogen. The first three open reading frames in this H. ducreyi gene cluster encoded predicted proteins with a high degree of identity to the Flp (fimbria-like protein) encoded by the first open reading frame of the tad locus; this 15-gene cluster in H. ducreyi was designated flp. RT-PCR analysis indicated that the H. ducreyi flp gene cluster was likely to be a polycistronic operon. Mutations within the flp gene cluster resulted in an inability to form microcolonies in the presence of human foreskin fibroblasts. In addition, the same mutants were defective in the ability to attach to both plastic and human foreskin fibroblasts in vitro. An H. ducreyi mutant with an inactivated tadA gene exhibited a small decrease in virulence in the temperature-dependent rabbit model for experimental chancroid, whereas another H. ducreyi mutant with inactivated flp-1 and flp-2 genes was as virulent as the wild-type parent strain. These results indicate that the flp gene cluster is essential for microcolony formation by H. ducreyi, whereas this phenotypic trait is not linked to the virulence potential of the pathogen, at least in this animal model of infection.

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“…To date, however, only three outer membrane antigens have been shown to be essential to the ability of H. ducreyi to produce an infection in human volunteers. These include the peptidoglycan-associated lipoprotein (23), the hemoglobinbinding outer membrane protein HgbA (6), and the DsrA protein, which is involved in serum resistance (12,20).…”

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Inhibition of Phagocytosis byHaemophilus ducreyiRequires Expression of the LspA1 and LspA2 Proteins

2003

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Haemophilus ducreyi previously has been shown to inhibit the phagocytosis of both secondary targets and itself by certain cells in vitro. Wild-type H. ducreyi strain 35000HP contains two genes, lspA1 and lspA2, whose encoded protein products are predicted to be 456 and 543 kDa, respectively. An isogenic mutant of H. ducreyi 35000HP with inactivated lspA1 and lspA2 genes has been shown to exhibit substantially decreased virulence in the temperature-dependent rabbit model for chancroid. This lspA1 lspA2 mutant was tested for its ability to inhibit phagocytosis of immunoglobulin G-opsonized particles by differentiated HL-60 and U-937 cells and by J774A.1 cells. The wild-type strain H. ducreyi 35000HP readily inhibited phagocytosis, whereas the lspA1 lspA2 mutant was unable to inhibit phagocytosis. Similarly, the wild-type strain was resistant to phagocytosis, whereas the lspA1 lspA2 mutant was readily engulfed by phagocytes. This inhibitory effect of wild-type H. ducreyi on phagocytic activity was primarily associated with live bacterial cells but could also be found, under certain conditions, in concentrated H. ducreyi culture supernatant fluids that lacked detectable outer membrane fragments. Both the wild-type strain and the lspA1 lspA2 mutant attached to phagocytes at similar levels. These results indicate that the LspA1 and LspA2 proteins of H. ducreyi are involved, directly or indirectly, in the antiphagocytic activity of this pathogen, and they provide a possible explanation for the greatly reduced virulence of the lspA1 lspA2 mutant.

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DsrA-Deficient Mutant of Haemophilus ducreyi Is Impaired in Its Ability To Infect Human Volunteers

Cited by 66 publications

References 42 publications

Characterization of the CpxRA Regulon in Haemophilus ducreyi

Characterization of the CpxRA Regulon in Haemophilus ducreyi

Haemophilus ducreyi Requires the flp Gene Cluster for Microcolony Formation In Vitro

Inhibition of Phagocytosis byHaemophilus ducreyiRequires Expression of the LspA1 and LspA2 Proteins

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