Pathogenesis & molecular epidemiology of Pneumococcal infection in Sickle Cell

发病

• 批准号: 7821228
• 负责人: Elaine I Tuomanen
• 金额: $ 30.43万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7821228
• 关键词: Affect; Anemia; Antibiotic Resistance; Antibiotic susceptibility; Antibiotics; Cell Wall; Child; Clinical; Clinical Research; Cohort Studies; Collaborations; Data; Disease; Disease Outcome; Encapsulated; Enrollment; Evolution; Genes; Genomics; Grant; Investigation; Iron; Microarray Analysis; Modeling; Molecular Epidemiology; Mutation; Operon; Pathogenesis; Patients; Pattern; Penicillins; Phenotype; Pneumococcal Infections; Pneumococcal conjugate vaccine; Pneumococcal vaccine; Population; Populations at Risk; Property; Prophylactic treatment; Proteins; Recording of previous events; Risk; Serotyping; Severities; Sickle Cell; Sickle Cell Anemia; Streptococcus pneumoniae; Surface; Testing; Translational Research; Transplantation; Vaccines; base; cohort; comparative genomic hybridization; experience; improved; mouse model; pathogen; platelet activating factor receptor; programs; receptor; trait; uptake

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. Over the previous grant cycle, a collaboration between the program in pneumococcal pathogenesis and the SS transplant mouse model has revealed the PAF receptor to be a key determinant of increased invasive disease. Specific receptor antagonists improve the outcome of disease. This provides a model to examine the bacterial and host determinants of severe disease to be studied in the next grant period. Building on a strong history of this Center's study of the colonization of SS patients with antibiotic resistant pneumococci, the effect of the new seven-valent conjugate pneumococcal vaccine on nasopharyngeal carriage with specific reference to antibiotic susceptibility and shifts away from vaccine serotypes is being studied. These studies may also have implications for the efficacy of continued penicillin prophylaxis in this at risk population. All cohorts for the study have been fully enrolled and will now be followed for the next grant period. Investigation of the genomic content of strains collected thusfar using microarrays has indicated that SS pneumococci that become invasive carry a specific set of genes, most notably related to iron transport. This property will be examined in the entire clinical cohort of strains and the relationship of the function of the locus to pathogenesis will be determined by mutational analysis and phenotype in the mouse model established in the first grant cycle.

镰状细胞病患者患严重肺炎球菌感染的风险增加 400 倍。 其他有荚膜病原体或其他贫血症不具有这种风险，这表明存在 肺炎球菌疾病的严重程度与 SS 表型之间的潜在因果关系。这 该申请旨在研究镰状细胞病中肺炎球菌感染的两个方面。超过 上一个拨款周期，肺炎球菌发病机制项目与 SS 之间的合作 移植小鼠模型揭示 PAF 受体是侵袭性增加的关键决定因素 疾病。特异性受体拮抗剂可改善疾病的结果。这提供了一个模型来检查 将在下一个资助期内研究严重疾病的细菌和宿主决定因素。 建立在该中心对抗生素耐药性 SS 患者定植研究的悠久历史之上 肺炎球菌，新型七价肺炎球菌结合疫苗对鼻咽部的影响 正在具体参考抗生素敏感性和远离疫苗血清型的携带 研究过。这些研究也可能对持续青霉素预防的疗效产生影响。 高危人群。该研究的所有队列均已完全入组，现在将进行下一个研究 授予期。使用微阵列对迄今为止收集的菌株的基因组内容进行了研究 表明具有侵袭性的 SS 肺炎球菌携带一组特定的基因，最显着的是与 铁运输。将在整个临床菌株队列中检查该特性以及它们之间的关系 该位点在发病机制中的功能将通过突变分析和表型来确定 在第一个资助周期建立的小鼠模型。