Pathogenesis and Molecular Epidemiology of Pneumococcal Infection in Sickle Cell

患有镰状细胞病的患者患严重肺炎球菌感染的风险增加400倍。这 其他包裹的病原体或其他贫血不具有共同的风险，这表明存在潜在的 肺炎链球菌病严重程度与SS表型的因果关系此应用程序旨在 调查镰状细胞病肺炎球菌感染的两个方面。首先，我们将利用 在本SS中心有肺炎球菌致病机制的项目和创建SS的专业知识 移植小鼠模型(项目4)。这两个计划将合作确定哪一步 肺炎球菌在野生型和SS小鼠之间的侵袭性不同。殖民和入侵的步骤将是 将在分子水平上进行解剖，并测试特定受体拮抗剂的干预作用。我们会 进一步确定进行性血液病提供的预防脑膜炎双球菌疾病的水平 通过移植矫正。 其次，我们将建立在该中心对SS患者的定植研究的强大历史基础上 耐药肺炎球菌。新型七价结合肺炎球菌疫苗的研制 进入党卫队种群的研究尚未见报道。我们将用以下方法确定其对鼻咽运输的影响 具体提到抗生素敏感性，而不是疫苗血清型。我们将进一步测量 临床分离株中出现了一种新的抗生素耐药特性。容忍防止 抗生素会杀死肺炎球菌，并可能对感染结果产生不利影响。这一财产的传播 可能对持续青霉素预防在这一高危人群中的有效性有影响。

Patients with sickle cell disease experience a 400 fold increased risk of severe pneumococcal infection. This risk is not shared by other encapsulated pathogens or by other anemias suggesting that there is a potentially causal relationship between severity of pneumococcal disease and the SS phenotype. This application seeks to investigate two aspects of pneumococcal infection in sickle cell disease. First we will take advantage of the presence in this SS Center of a program in pneumococcal pathogenesis and expertise in creating an SS transplant mouse model (Project 4). These two programs will cooperate to characterize which step in pneumococcal invasion differs between wild type and SS mice. The steps of colonization and invasion will be dissected at the molecular level and intervention with specific receptor antagonists will be tested. We will further determine the level of protection from pneurnococcal disease afforded by progressive hematologic correction by transplantation. Second we will build on a strong history of this Center's study of the colonization of SS patients with antibiotic resistant pneumococci. The introduction of the new seven-valent conjugate pneumococcal vaccine into the SS population has not been studied. We will determine its effect on nasopharyngeal carriage with specific reference to antibiotic susceptibility and shifts away from vaccine serotypes. Further we will measure the prevalence of a new property of antibiotic tolerance emerging in clinical isolates. Tolerance prevents antibiotic killing of pneumococci and may adversely affect the outcome of infection. Spread of this property may have implications for the efficacy of continued penicillin prophylaxis in this at risk population.