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续取决于其与其他物种以及同一物种成员竞争的能力。抗生素和疫苗等手段改变了这些关系的动态，有时会产生不良后果。最近引入的肺炎链球菌结合疫苗降低了这一主要病原体对所包括血清型的携带和疾病负担。然而，用非疫苗血清型替代的问题日益严重，这表明疫苗已经减轻了抑制这些以前不太常见的血清型的竞争性选择压力。因此，临床经验揭示了该物种种内竞争的重要性，以及更好地了解影响其因素的必要性，以便维持或改进其他成功的预防策略。这种种内竞争的机制可能是基于肺炎球菌细菌素（肺炎素）的合成。这些由blp基因座表达的小抗菌肽针对的是同一物种中不产生同源免疫蛋白的成员。在小鼠定植模型中，肺炎素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性肺炎素的分离株，该分离株抑制所有其他测试的肺炎球菌。在Specific Aim #1中，我们将描述促进种内竞争的广泛作用肺炎素。具体来说，我们将1)确定广泛作用的肺炎素和对这些肺炎素的免疫基础，2)确定肺炎素及其免疫对临床分离株竞争的贡献，以及3)测试这些肺炎素是否可用于减少肺炎球菌定植。我们还表明，表达相同的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，东道主因素也可以决定竞争的结果。因此，在特异性目标#2中，我们将确定宿主先天免疫反应和对这些反应的不同细菌耐药性是否有助于定植过程中的种内竞争。我们将重点讨论肺炎球菌清除的主要机制，包括补体和吞噬细胞；而主要毒力因子和决定抗清除能力的因素，则是胶囊类型，来决定它们在竞争中的作用。定义这两种不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占上风的原因提供分子解释。公共卫生相关性：最近引入的儿童肺炎链球菌疫苗已经改变了致病菌株的谱，并揭示了竞争平衡对该物种生态和疾病预防的重要性。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)描述针对同一物种成员的称为细菌素的细菌因子的详细描述，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.