The Immunobiology of the Hemoglobin Receptor of H. ducreyi

杜克雷血红蛋白受体的免疫生物学

• 批准号: 7315873
• 负责人: CHRISTOPHER ELKINS
• 金额: $ 29.56万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7315873
• 关键词: Address; Adjuvant; Adjuvant Study; Affinity Chromatography; Africa; Animal Model; Animals; Antibodies; Antibody Formation; Antigenic Variation; Antigens; Asia; Bacteria; Binding; Blocking Antibodies; Cell Line; Class; Complement; Data; Developed Countries; Developing Countries; Disease; Epitopes; Escherichia coli; Event; Experimental Models; Family suidae; Freund' s Adjuvant; Future; General Population; Genital system; Goals; HIV; Heme; Hemoglobin; Hemophilus ducreyi; Heterosexuals; Histology; Human; Humoral Immunities; Immune; Immune Sera; Immunity; Immunization; Immunobiology; Immunoglobulin G; Immunology; In Vitro; Infection; Intervention; Laboratories; Lead; Ligands; Mediating; Methods; Modeling; Nature; Nutrient; Organism; Passive Immunization; Phase; Plasmids; Principal Investigator; Prostitution; Proteins; Public Health; Recombinants; Reporting; Resistance; Respiratory Burst; Role; Sepharose; Serum; Source; Starvation; Surface; Sus scrofa; System; Testing; Ulcer; Vaccines; Virulence Factors; Virulent; Work; absorption; bactericide; design; extracellular; human study; in vivo; killings; mutant; neutrophil; programs; receptor; research study; transmission process; vaccine development

DESCRIPTION (provided by applicant): Haemophilus ducreyi, the etiologic agent of the genital ulcer disease chancroid is a significant public health problem in several regions worldwide. In developing countries of Africa, Asia and other continents, it is an important co-factor for the heterosexual transmission of HIV. Control of chancroid, using an effective vaccine that is properly administered to the core group of commercial sex workers that serve as a reservoir, would likely reduce HIV transmission in the general population. It is the goal of my laboratory to develop such a vaccine. We propose to continue our vaccine studies on the hemoglobin receptor (HgbA) of H. ducreyi. Several attributes of HgbA make it an attractive vaccine candidate. HgbA is required to establish human experimental infection. HgbA is conserved immunologically and functionally and all virulent H. ducreyi strains express it. Unlike hemoglobin receptors from other bacteria, HgbA does not undergo phase or antigenic variation. Our recent studies in the swine model of chancroid infection, that closely resembles natural human infection, demonstrate that purified native HgbA is a highly effective vaccine. Additional vaccine studies proposed here will be undertaken using recombinant (rHgbA). We will test the ability of HgbA vaccines to protect against homologous and heterologous challenge infections using various non-toxic adjuvants. We will begin to address the mechanism of protection by the HgbA vaccine. We will perform classical passive transfer of IgG to formally prove that the protection observed is antibody-mediated. We will determine role of neutrophils in the killing of H. ducreyi opsonized with HgbA antibodies, identify the domain(s) of HgbA that are necessary for binding its ligand human hemoglobin, and identify regions of HgbA that elicit bactericidal antibodies. These studies are critical to rational vaccine development for chancroid.

描述（由申请人提供）：生殖器溃疡病冠状动脉疾病的病因学代理Heamophilus Ducreyi在全球几个地区都是一个重大的公共卫生问题。在非洲，亚洲和其他大陆的发展中国家中，它是艾滋病毒异性传播的重要联合因素。使用有效的疫苗，该疫苗适当地施用给担任储层的商业性工作者核心群体，可能会减少普通人群中的HIV传播。我的实验室是开发这种疫苗的目标。我们建议继续对H. ducreyi的血红蛋白受体（HGBA）进行疫苗研究。 HGBA的几个属性使其成为有吸引力的疫苗候选者。需要HGBA建立人类实验感染。 HGBA在免疫学和功能上是保守的，所有有毒的H. ducreyi菌株表达了它。与其他细菌的血红蛋白受体不同，HGBA不会发生相或抗原差异。我们最近在类似于自然的人类感染的猪的猪模型中的研究表明，纯化的天然HGBA是一种高效的疫苗。此处提出的其他疫苗研究将使用重组（RHGBA）进行。我们将测试HGBA疫苗使用各种无毒佐剂预防同源和异源挑战感染的能力。我们将开始解决HGBA疫苗保护机制。我们将进行IgG的经典被动转移，以正式证明观察到的保护是抗体介导的。我们将确定嗜中性粒细胞在用HGBA抗体调子杀死二氏菌的作用，确定HGBA的结构域，这些结构域是结合其配体人类血红蛋白所必需的，并确定引起杀菌性抗体的HGBA区域。这些研究对于理性疫苗的开发至关重要。