The Immunobiology of the Hemoglobin Receptor of H. ducreyi

描述（由申请方提供）：杜克雷嗜血杆菌是生殖器溃疡疾病软下疳的病原体，在全球多个地区是一个重要的公共卫生问题。在非洲、亚洲和其他大陆的发展中国家，它是异性性传播艾滋病毒的一个重要辅助因素。控制软下疳，使用有效的疫苗，适当地给予作为储库的商业性工作者的核心群体，可能会减少艾滋病毒在一般人群中的传播。我的实验室的目标就是研制这样一种疫苗。我们建议继续我们的疫苗研究血红蛋白受体（HgbA）的H。ducreyi。HgbA的几个属性使其成为一种有吸引力的候选疫苗。HgbA是建立人类实验感染所必需的。HgbA在免疫学和功能上是保守的，所有致病性H.与来自其他细菌的血红蛋白受体不同，HgbA不经历相位或抗原变异。我们最近在猪软下疳感染模型中的研究，非常类似于自然的人类感染，证明纯化的天然HgbA是一种非常有效的疫苗。本文提出的其他疫苗研究将使用重组（rHgbA）进行。我们将使用各种无毒佐剂测试HgbA疫苗保护免受同源和异源攻击感染的能力。我们将开始探讨甲型肝炎疫苗的保护机制。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。我们将确定中性粒细胞在杀死H.用HgbA抗体调理的ducreyi，鉴定结合其配体人血红蛋白所必需的HgbA结构域，并鉴定引发杀菌抗体的HgbA区域。这些研究对软下疳疫苗的合理开发至关重要。

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.