Haemophilus ducreyi, the etiological agent of the genital ulcer disease chancroid, is a significant public health problem in several regions woridwide. We propose to continue structure/function studies of the outer membrane protein DsrA of H. ducreyi and determine its vaccine potential. The long-term goal of this research is to develop a vaccine against chancroid. DsrA is a multifunctional trimeric autotransporter protein conferring high levels of serum resistance to H. ducreyi. Additionally, DsrA binds the extracellular matrix components fibronectin and vitronectin and confers upon H. ducreyi the ability to attach to keratinocytes. Each of these 4 functions of DsrA is considered a virulence factor in other bacterial systems.
Specific aim 1 proposes to continue investigating the structural components of DsrA involved in its multiple functions. The domain(s) required for keratinocyte binding will be identified using a panel of dsrA mutants. The specific residues required for each of the 4 functions of DsrA will also be pinpointed using peptide libraries and site-directed mutagenesis. Defined dsrA mutants will be tested in the experimental human model of chancroid to determine which function of DsrA is required for infection. The results from these experiments will focus and inform efforts for the vaccine studies described in aim 2.
Specific aim 2 proposes to determine if DsrA is an effective vaccine in the experimental swine model of chancroid. Active immunization with rDsrA or passive immunization with an anti-DsrA monoclonal antibody will be done to examine the efficacy of DsrA as a vaccine against chancroid. Non-toxic adjuvants will be examined as substitutes for Freund's adjuvant.
In developing countries of Africa, Asia and other continents, chancroid is an important co-factor for the heterosexual transmission of HIV. Furthermore, increasing antibiotic resistance of H. ducreyi can negatively impact chancroid treatment. Control of chancroid, using a properiy administered effective vaccine, would likely reduce chancroid incidence and HIV transmission
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