Abstract
BackgroundBacterial lipoproteins often play important roles in pathogenesis and can stimulate protective immune responses. Such lipoproteins are viable vaccine candidates. Haemophilus ducreyi, which causes the sexually transmitted disease chancroid, expresses a number of lipoproteins during human infection. One such lipoprotein, OmpP4, is homologous to the outer membrane lipoprotein e (P4) of H. influenzae. In H. influenzae, e (P4) stimulates production of bactericidal and protective antibodies and contributes to pathogenesis by facilitating acquisition of the essential nutrients heme and nicotinamide adenine dinucleotide (NAD). Here, we tested the hypothesis that, like its homolog, H. ducreyi OmpP4 contributes to virulence and stimulates production of bactericidal antibodies.ResultsWe determined that OmpP4 is broadly conserved among clinical isolates of H. ducreyi. We next constructed and characterized an isogenic ompP4 mutant, designated 35000HPompP4, in H. ducreyi strain 35000HP. To test whether OmpP4 was necessary for virulence in humans, eight healthy adults were experimentally infected. Each subject was inoculated with a fixed dose of 35000HP on one arm and three doses of 35000HPompP4 on the other arm. The overall parent and mutant pustule formation rates were 52.4% and 47.6%, respectively (P = 0.74). These results indicate that expression of OmpP4 in not necessary for H. ducreyi to initiate disease or progress to pustule formation in humans. Hyperimmune mouse serum raised against purified, recombinant OmpP4 did not promote bactericidal killing of 35000HP or phagocytosis by J774A.1 mouse macrophages in serum bactericidal and phagocytosis assays, respectively.ConclusionsOur data suggest that, unlike e (P4), H. ducreyi OmpP4 is not a suitable vaccine candidate. OmpP4 may be dispensable for virulence because of redundant mechanisms in H. ducreyi for heme acquisition and NAD utilization.
Highlights
Bacterial lipoproteins often play important roles in pathogenesis and can stimulate protective immune responses
Based on sorting signals described for Escherichia coli, the presence of a tyrosine at position 2 suggests that outer membrane protein P4 (OmpP4) sorts to the outer membrane [22,23]
PCR amplification of the open reading frame (ORF) of ompP4 demonstrated that the gene was conserved in size and location among 10 different strains of H. ducreyi (Figure 1)
Summary
Bacterial lipoproteins often play important roles in pathogenesis and can stimulate protective immune responses. Haemophilus ducreyi, which causes the sexually transmitted disease chancroid, expresses a number of lipoproteins during human infection. One such lipoprotein, OmpP4, is homologous to the outer membrane lipoprotein e (P4) of H. influenzae. Lipoproteins have been demonstrated to Haemophilus ducreyi, the etiologic agent of the sexually transmitted genital ulcer disease chancroid, has the capacity to express 67 putative lipoproteins (GenBank accession number AE017143), only four of which have been well characterized: the peptidoglycan associated lipoprotein (PAL), the fibrinogen binding protein (FgbA), the ducreyi lectin A (DltA), and H. ducreyi lipoprotein (Hlp) [5,6,7]. The roles of other lipoproteins in H. ducreyi pathogenesis have not yet been delineated
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