THE MOLECULAR BASIS OF HAEMOPHILUS DUCREYI PATHOGENESIS

性状（改编自申请人摘要）：杜克雷嗜血杆菌， 生殖器溃疡疾病软下疳的病原体，是一种新兴的 细菌病原体在美国。 这种生物长期以来 被认为是一种重要的性传播病原体， 尤其是在东南亚和非洲。 无论其 世界范围内的流行，以及H.杜克雷伊感染显著 增强异性恋艾滋病毒传播，这种生物可以说是最少的 了解性传播病原体。 的长期目标 这个项目是建立H的独特方面的基础。 ducreyi宿主相互作用，从而更好地了解这是如何 微生物导致疾病，并有助于艾滋病毒的传播。 具体目标#1：宿主免疫细胞和细胞因子的模式是什么 响应H。ducreyi感染？ 这一目标基于以下假设： H. ducreyi最初与宿主角质形成细胞相互作用， 特异性细胞因子的表达，特别是IL-8， 软下疳发病机制 调查人员将检查这一影响， 细胞因子对PMN迁移的诱导作用以及细菌对H. ducreyi在感染的人工体外皮肤模型中。 具体目标#2：哪些宿主细胞与H相关。ducreyi和什么 这种病原体是否表达了宿主细胞的结合机制？ 这 目的是基于假设H. ducreyi存在于 在宿主中的基底上角质形成细胞，以及表达的特定产物 促进粘附和侵入人角质形成细胞。 H.将在人造皮肤中检查ducreyi-宿主细胞协会 猪感染模型。 一系列遗传学程序，包括 基因克隆和诱变将用于确定病原体特异性 H所需的组件。ducreyi与宿主细胞的相互作用。 具体目标#3：输出的CuZn SOD如何有助于H。杜克雷 发病机制？ 本实验验证了H. ducreyi出口CuZn SOD保护这种生物体免受杀菌 宿主产生的超氧化物的影响。 野生型的相对存活率 和突变体H.缺乏输出SOD的ducreyi暴露于中性粒细胞， 人工皮肤模型将被确定。 输出的SOS在 H.将在猪中评价Ducreyi存活和病变发展 使用正常和消瘦猪的软下疳模型。

DESCRIPTION (Adapted from the applicant's abstract): Haemophilus ducreyi, the etiologic agent of the genital ulcer disease chancroid, is an emerging bacterial pathogen in the United States. This organism has long been recognized as a significant sexually transmitted pathogen in other parts of the world, particularly in southeast Asia and Africa. Regardless of its world-wide prevalence, and the fact that H. ducreyi infections significantly enhance heterosexual HIV transmission, this organism is arguably the least understood of the sexually transmitted pathogens. The long-term goal of this project is to establish the basis for the unique aspects of H. ducreyi-host interactions, and thus a better understanding of how this organism causes disease and contributes to HIV transmission. Specific Aim #1: What is the pattern of host immune cell and cytokine response to H. ducreyi infection? This aim is based on the hypothesis that H. ducreyi initially interact with host keratinocytes provoking the expression of specific cytokines, IL-8 in particular, that contribute to chancroid pathogenesis. The investigators will examine the effects of this cytokine induction on PMN migration and bacterial activity against H. ducreyi in an artificial in vitro skin model of infection. Specific Aim #2: What host cells are associated with H. ducreyi and what are the host cell association mechanisms expressed by this pathogen? This aim is based on the hypothesis that H. ducreyi are present within the suprabasal keratinocytes in the host, and that specific products expressed by this organism promote adherence to, and invasion of, human keratinocytes. H. ducreyi-host cell associations will be examined in the artificial skin and swine infection models. A combination of genetic procedures including gene cloning and mutagenesis will be used to determine the pathogen-specific components required for H. ducreyi interactions with host cells. Specific Aim #3: How does the exported CuZn SOD contribute to H. ducreyi pathogenesis? The experiments in this aim test the hypothesis that the H. ducreyi exported CuZn SOD protects this organism from the bactericidal effects of host-generated superoxide. The relative survival of wild type and mutant H. ducreyi lacking the exported SOD exposed to neutrophils in the artificial skin model will be determined. The role of the exported SOS in H. ducreyi survival and lesion development will be evaluated in the swine model of chancroid using both normal and neutropenic pigs.