Bacterial and host factors in pneumococcal competition

肺炎球菌竞争中的细菌和宿主因素

• 批准号: 7751906
• 负责人: Jeffrey Neal Weiser
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-25 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7751906
• 关键词: Affect; Alleles; Antibiotics; Carrier State; Childhood; Clinical; Communities; Complement; Conjugate Vaccines; Data; Disease; Ecology; Equilibrium; Human; Immune response; Immunity; In Vitro; Infection; Inflammation; Integration Host Factors; Laboratories; Mediating; Microbe; Molecular; Outcome; Phagocytes; Pneumococcal Colonization; Pneumonia; Population; Post-Transcriptional Regulation; Prevalence; Prevention strategy; Proteins; Reapplication; Reporting; Resistance; Respiratory System; Respiratory tract structure; Role; Serotyping; Specificity; Streptococcus pneumoniae; Surface; Systemic infection; Testing; Vaccination; Vaccines; Virulence Factors; antimicrobial peptide; bacterial resistance; bacteriocin; base; capsule; disorder prevention; experience; improved; in vivo; killings; member; microorganism; mouse model; novel strategies; pathogen; pressure; public health relevance; response; success

DESCRIPTION (provided by applicant): The establishment and persistence of a microbe on a host surface will depend on its ability to compete with other species as well as members of the same species. Manipulations, such as antibiotics and vaccines, alter the dynamics of these relationships, sometimes with undesirable consequences. Recent introduction of a conjugate vaccine for Streptococcus pneumoniae has lowered the burden of carriage and disease by this leading pathogen for the included serotypes. However, the growing problem of replacement with non-vaccine serotypes shows that the vaccine has diminished the competitive selective pressure that had been suppressing these previously less common serotypes. Clinical experience, therefore, has revealed the importance of intraspecies competition for this species and the need to better understand factors affecting it in order to maintain or improve an otherwise successful prevention strategy. A mechanism that may underlie this intraspecies competition is based on the elaboration of pneumococcal bacteriocins (pneumocins). These small antimicrobial peptides expressed by the blp locus target members of the same species that do not produce a cognate immunity protein. In the mouse model of colonization, pneumocins dictate the outcome of competition between two isolates. We have identified isolates expressing broadly active pneumocins that inhibit all other pneumococci tested. In Specific Aim #1, we will characterize the broadly acting pneumocins that contribute to intraspecies competition. Specifically, we will 1) identify the broadly acting pneumocins and the basis of immunity to these pneumocins, 2) determine the contribution of pneumocins and their immunity to competition among clinical isolates, and 3) test whether these pneumocins can be used to reduce pneumococcal colonization. We have also shown that isolates expressing the same pneumocin alleles and lacking direct bacterial-bacterial inhibition are still able to compete in vivo. Preliminary data, therefore, indicates that host factors can also dictate the outcome of competition. Thus, in Specific Aim #2 we will determine whether host innate immune responses and differential bacterial resistance to these responses contribute to intraspecies competition during colonization. We will focus on the major mechanisms of pneumococcal clearance, involving complement and phagocytes; and the major virulence factor and determinant of resistance to clearance, capsule type, to determine their role in competition. Defining these two non-mutually exclusive mechanisms of competition, involving the elaboration of anti-pneumococcal factors by competing pneumococci or by the host, will provide a molecular explanation for why some pneumococcal strains or types prevail. PUBLIC HEALTH RELEVANCE: The recent introduction of childhood vaccination against Streptococus pneumoniae has altered the spectrum of disease-causing strains and revealed the importance of the competitive balance for the ecology of this species and prevention of disease. The focus of this project is to define how competition occurs for this leading human pathogen. The project will 1) characterize the elaboration of bacterial factors called bacteriocins that target members of the same species and 2) define how this pathogen takes advantage of the host immune response to promote its competitive success.

描述（由申请人提供）：微生物在宿主表面上的建立和持久性将取决于其与其他物种以及同一物种成员竞争的能力。抗生素和疫苗等操纵改变了这些关系的动态，有时会产生不良后果。最近引入了用于肺炎链球菌的结合疫苗通过这种领先的血清型来减轻运输和疾病的负担。但是，用非疫苗血清型替代的日益增长的问题表明，该疫苗已经降低了抑制这些以前不常见的血清型的竞争性选择压力。因此，临床经验揭示了种内竞争对该物种的重要性，并且需要更好地理解影响它的因素，以维持或改善原本成功的预防策略。可能是这种种内竞争的基础的机制是基于肺炎球菌（肺炎蛋白）的阐述。这些由BLP基因座靶构件表达的这些小抗菌肽，这些肽的同一物种不产生同类免疫蛋白。在定植的小鼠模型中，肺炎蛋白决定了两个分离株之间竞争的结果。我们已经确定了表达广泛活跃的肺气素的分离株，这些肺炎蛋白抑制了所有其他肺炎球菌。在特定的目标＃1中，我们将表征有助于种子内竞争的广泛作用的肺气素。具体而言，我们将1）确定广泛作用的肺炎蛋白和对这些肺炎蛋白的免疫力，2）确定肺炎蛋白的贡献及其对临床分离株之间竞争的贡献，以及3）测试这些肺炎蛋白是否可以用于减少肺炎球菌的降低。我们还表明，表达相同肺炎素等位基因和缺乏直接细菌细菌抑制的分离株仍然能够在体内竞争。因此，初步数据表明，宿主因素也可以决定竞争的结果。因此，在特定的目标＃2中，我们将确定宿主先天免疫反应和对这些反应的差异细菌抗性是否有助于定植期间的种内竞争。我们将重点关注肺炎球菌清除的主要机制，涉及补体和吞噬细胞。以及胶囊类型的耐药性的主要毒力因素和决定因素，以确定其在竞争中的作用。定义竞争的这两种非单纯性排斥机制，涉及通过竞争性肺炎球或宿主阐述抗波经菌因子，将提供一个分子解释，说明为什么某些肺炎球菌菌株或类型为何预期。公共卫生相关性：最近引入针对肺炎链球菌的儿童疫苗接种改变了引起疾病的菌株的范围，并揭示了竞争平衡对这种物种的生态学和预防疾病的重要性。该项目的重点是定义这种领先的人类病原体的竞争如何发生。该项目将以1）为靶向同一物种的成员的细菌因子的精确表征，以及2）定义该病原体如何利用宿主免疫反应来促进其竞争成功。