H. ducreyi Pathogenesis (DltA, DsrA and variants)

杜氏嗜血杆菌是生殖器溃疡软下疳病的病原，是世界上一些地区的一个重大公共卫生问题。在非洲、亚洲和其他发展中国家，它是艾滋病毒异性传播的重要辅助因素。控制软下疳，使用有效的疫苗，适当的管理，可能会减少艾滋病毒的传播。我们建议研究杜氏分枝杆菌与宿主细胞、细胞外基质成分（ECMs）和血清蛋白的相互作用。对大多数病原微生物来说，附着在宿主细胞上是感染过程中至关重要的第一步。在附着之后，抵抗正常人血清抗体和补体的杀菌活性的能力是第二个重要的毒力因子。我的实验室已经确定了两种外膜蛋白，DsrA和DltA，它们对杜氏嗜血杆菌的血清抗性表达至关重要。此外，DsrA和可能的DltA是H. ducreyi附着于皮肤细胞和ecm的重要配体。DsrA突变体在人类和动物感染模型中是无毒的，但目前尚不清楚这种毒性是否存在

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.