Pathogenesis and Molecular Epidemiology of Pneumococcal Infection in Sickle Cell

镰状细胞病患者经历严重肺炎球菌感染的风险增加400倍。这 其他包囊病原体或其他贫血不具有相同的风险，这表明存在潜在的 肺炎球菌疾病的严重程度和SS表型之间的因果关系。本申请旨在 调查镰状细胞病中肺炎球菌感染的两个方面。首先，我们将利用 存在于这个SS中心的肺炎球菌发病机制和专业知识，在创建一个SS 移植小鼠模型（项目4）。这两个程序将合作确定 肺炎球菌侵袭在野生型和SS小鼠之间不同。殖民和入侵的步骤将是 将在分子水平上进行剖析，并测试用特异性受体拮抗剂进行干预。我们将 进一步确定进行性血液学检查提供的对肺炎球菌病的保护水平， 通过移植进行矫正。 其次，我们将建立在这个中心的SS患者的殖民化研究的强大历史， 抗生素耐药肺炎球菌新七价肺炎球菌结合疫苗的推出 对党卫军的研究还没有进行过。我们将确定其对鼻咽携带的影响， 具体参考抗生素敏感性和从疫苗血清型转移。我们将进一步衡量 在临床分离株中出现的抗生素耐药性的新特性的流行。宽容防止 抗生素杀死肺炎球菌，并可能对感染的结果产生不利影响。此属性的扩展 这可能对在这一高危人群中继续进行青霉素预防的有效性有影响。

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.