Bacterial and host factors in pneumococcal competition

描述（由申请人提供）：微生物在宿主表面的建立和持久性将取决于其与其他物种以及相同物种成员竞争的能力。抗生素和疫苗等操纵手段改变了这些关系的动态，有时会带来不良后果。最近引入的肺炎链球菌结合疫苗降低了所包括血清型的这种主要病原体的携带和疾病负担。然而，越来越多的非疫苗血清型的替代问题表明，疫苗已经减少了竞争选择压力，抑制了这些以前不太常见的血清型。因此，临床经验揭示了种内竞争对该物种的重要性，并且需要更好地了解影响它的因素，以维持或改善其他成功的预防策略。一种可能导致这种种内竞争的机制是基于肺炎球菌细菌素（pneumococins）的加工。这些由blp基因座表达的小的抗微生物肽靶向不产生同源免疫蛋白的相同物种的成员。在小鼠模型中的殖民化，mecins决定了两个分离株之间的竞争结果。我们已经鉴定了表达广泛活性的肺炎球菌素的分离株，这些肺炎球菌素抑制所有其他测试的肺炎球菌。在具体目标#1中，我们将描述有助于种内竞争的广泛作用的多环芳烃。具体而言，我们将1）鉴定广泛作用的肺炎球菌素和对这些肺炎球菌素的免疫基础，2）确定肺炎球菌素及其免疫力对临床分离株之间竞争的贡献，3）测试这些肺炎球菌素是否可用于减少肺炎球菌定殖。我们还表明，表达相同肺炎菌素等位基因且缺乏直接细菌-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，东道主因素也可以决定竞争的结果。因此，在具体目标#2中，我们将确定宿主先天免疫应答和对这些应答的差异细菌抗性是否有助于定殖期间的种内竞争。我们将重点介绍肺炎球菌清除的主要机制，包括补体和吞噬细胞;以及主要的毒力因子和清除抵抗的决定因素，荚膜类型，以确定它们在竞争中的作用。定义这两种非相互排斥的竞争机制，包括竞争性肺炎球菌或宿主对抗肺炎球菌因子的阐述，将为某些肺炎球菌菌株或类型的流行提供分子解释。公共卫生相关性：最近引入的儿童肺炎链球菌疫苗接种已经改变了致病菌株的谱，并揭示了该物种的生态和预防疾病的竞争平衡的重要性。该项目的重点是确定这种主要人类病原体的竞争是如何发生的。该项目将1）描述称为细菌素的细菌因子的详细说明，这些细菌因子针对同一物种的成员，2）定义这种病原体如何利用宿主免疫反应来促进其竞争成功。

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.