HAEMOPHILUS INFLUENZAE B VIRULENCE: ROLE OF HAEMOCIN

描述（改编自申请人摘要）：H。流感是一种 人类特异性细菌病原体导致多种严重 儿童感染，包括肺炎、蜂窝织炎、脓毒性关节炎， 和会厌炎 此外，H。流感是最常见的原因 在美国，细菌性脑膜炎影响了大约12，000人， 孩子们每年 尽管最近在抗菌治疗方面取得了进展， 发病率和死亡率由H.流感感染已经改变 在过去的十年里很少。 两个因素清楚地区分了 H.从相对无毒引起侵袭性感染的流感 本种成员：存在多糖荚膜组成 聚核糖基核糖醇磷酸（PRP）和细菌素的生产 一种叫做血红素的蛋白质 尽管PRP胶囊已经广泛应用于 作为一种毒力因子，血菌素的作用还没有被证实。 研究了 该建议旨在研究血红素在致病性中的作用， H.流感。 为了明确地定义这一作用， 将确定血菌素的产量，并确定编码血菌素的基因 将被克隆。 将对克隆的血红素基因进行诱变 构建H.流感病毒的区别仅在于 产生血红素的能力。 这些同基因菌株将用于 通过使用一种 H.流感感染。 相对能力 HMC+和HMC-菌株的定殖和侵入乳鼠将是 评估。 该项目的另一个目标是纯化和表征 血红素蛋白 血红素在促进 通过介导对哺乳动物宿主细胞的直接毒性作用， 通过研究血红素产生对 相关人体组织的体外研究 如果血红素证明在 毒力、克隆的haemocin基因及其蛋白的可用性 产品将允许进一步的研究，旨在定义新的 预防H.流感感染。

DESCRIPTION (Adapted from applicant's abstract): H. influenzae is a human-specific bacterial pathogen responsible for a variety of serious infections in children, including pneumonia, cellulitis, septic arthritis, and epiglottitis. Further, H. influenzae is the most common cause of bacterial meningitis in the United States, affecting approximately 12,000 children annually. Despite recent advances in antimicrobial therapy, the morbidity and mortality resulting from H. influenzae infection has changed little during the past decade. Two factors clearly distinguish strains of H. influenzae which cause invasive infection from relatively avirulent members of this species: the presence of polysaccharide capsule composed of polyribosyl ribitol phosphate (PRP) and the production of a bacteriocin protein termed haemocin. Whereas the PRP capsule has been extensively examined as a virulence factor, the role of haemocin has not been investigated. This proposal seeks to investigate the role of haemocin in the virulence of H. influenzae. To unambiguously define this role, the genetic basis of haemocin production will be determined, and the gene(s) encoding haemocin will be cloned. Mutagenesis of the cloned haemocin gene will be performed to construct isogeneic strains of H. influenzae differing only in their ability to produce haemocin. These isogeneic strains will then be used to determine the effect of haemocin production in virulence by using a relevant animal model of H. influenzae infection. The relative abilities of HMC+ and HMC-strains to colonize and to invade infant rats will be assessed. Another goal of this project is to purify and characterize the haemocin protein. The potential role of haemocin in contributing to virulence by mediating a direct toxic effect upon mammalian host cells will be examined by investigating the effects of haemocin production upon relevant human tissue in vitro. Should haemocin prove important in virulence, the availability of the cloned haemocin gene and its protein product will permit further investigations designed to define new strategies for the prevention of H. influenzae infection.