H. ducreyi Pathogenesis (DltA, DsrA and variants)

H. ducreyi 发病机制（DltA、DsrA 和变种）

• 批准号: 6866275
• 负责人: CHRISTOPHER ELKINS
• 金额: $ 23.98万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6866275
• 关键词: HIV infections; Haemophilus ducreyi; adhesin; cooperative study; disease /disorder proneness /risk; extracellular matrix; human tissue; immunity; integrins; laboratory rabbit; lectin; pathologic process; protein structure function; sexually transmitted diseases; skin infection

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.

生殖器性溃疡病神经症的病因学剂Heamophilus Ducreyi在全球多个地区是一个重大的公共卫生问题。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联合因素。使用适当管理的有效疫苗控制牙头治疗可能会减少HIV传播。我们提出了关于杜卡里氏菌与宿主细胞，细胞外基质成分（ECM）和血清蛋白相互作用的研究。对于大多数致病性微生物的传染性过程，宿主细胞上的附着是关键的第一步。附着后，抗药的能力是正常人血清抗体和补体的杀菌活性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，这对于在H. ducreyi中表达血清抗性至关重要。此外，DSRA和可能的DLTA是针对皮肤细胞和ECM的H. ducreyi的重要配体。 DSRA突变体在感染的人类和动物模型中是无毒的，但尚不清楚这种气势是否是 由于无法附着或抵抗血清的杀菌作用。将对DSRA和DLTA进行详细研究，包括了解其血清的机制 反抗。我们将确定血清耐药性，角质形成细胞和ECM附着以及表面暴露的区域/残基。将构造DSRA的突变体，这些突变体耐血清，但无法附着在圆锥形细菌和/或宿主ECM上。我们将确定一个这样的突变体在人类感染模型中是否具有感染性。该实验将阐明体外和体内附着研究的明显差异。 DLTA在结构和功能上与ricinβ链有关。两者都是含有糖蛋白的乳糖的特异性。 DLTA与Ricin的相似性表明，像Ricin一样，DLTA也是粘合剂。我们将测试DLTA介导对宿主细胞和ECM的附着的能力。这些研究对于更好地理解牙冠发病机理非常重要，并将促进多个方面的疫苗发育。