H. ducreyi Pathogenesis (DltA, DsrA and variants)

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Haemophilus ducreyi, the etiologic agent of the genital ulcer disease chancroid, is a significant public health problem in several regions worldwide. In Africa, Asia and other developing countries, it is an important co-factor for the heterosexual transmission of HIV. Control of chancroid, using an effective vaccine that is properly administered, would likely reduce HIV transmission. We propose studies on the interaction of H. ducreyi with host cells, extracellular matrix components (ECMs) and serum proteins. Attachment to host cells is a critical first step in the infectious process for most pathogenic microbes. After attachment, the ability to resist the bactericidal activity of normal human serum antibody and complement is a second important virulence factor. My lab has identified two outer membrane proteins, DsrA and DltA, that are critical for expression of serum resistance in H. ducreyi. Furthermore, DsrA and possibly DltA, are important ligands for H. ducreyi attchment to skin cells and ECMs. DsrA mutants are avirulent in human and animal models of infection, but it is not known whether this avirulence is due to the inability to attach or to resist the bactericidal action of serum. Detailed studies will be undertaken on DsrA and DltA, including understanding their mechanisms of serum resistance. We will identify regions/residues of DsrA that are required for serum resistance, keratinocyte and ECM attachment and those that are surface-exposed. Mutants of dsrA will be constructed which are serum resistant but are unable to attach to keratinoctyes and/or host ECMs. We will determine whether one such mutant is infectious in the humans model of infection. This experiment will clarify the apparent discrepancy of in vitro and in vivo attachment studies. DltA is a lectin structurally and functionally related to the ricin Beta chain; both are specfic for lactose containing glycoproteins. The similarity of DltA to ricin suggest that like ricin, DltA is an adhesin. We will test the ability of DltA to mediate attachment to host cells and ECMs. These studies are important for better understanding of chancroid pathogenesis and will facilitate vaccine development in several aspects.