Bacterial and host factors in pneumococcal competition

描述(申请人提供)：微生物在宿主表面的建立和存留将取决于它与其他物种以及同一物种的成员竞争的能力。抗生素和疫苗等操作改变了这些关系的动态，有时会产生令人不快的后果。最近推出的肺炎链球菌结合疫苗降低了这种主要病原体对所包括的血清型的携带和疾病负担。然而，越来越多的用非疫苗血清型替代的问题表明，疫苗已经减少了竞争选择压力，这种压力一直在抑制这些以前不太常见的血清型。因此，临床经验揭示了该物种种内竞争的重要性，以及需要更好地了解影响竞争的因素，以便维持或改进原本成功的预防策略。这种种内竞争的一种机制可能是基于肺炎球菌细菌素的阐述。这些由BLP基因座表达的小抗菌肽针对的是不产生同源免疫蛋白的同一物种的成员。在定植的小鼠模型中，气球菌素决定了两个分离物之间竞争的结果。我们已经确定了表达广泛活性肺炎球蛋白的分离株，这些分离株对所有测试的其他肺炎球菌都有抑制作用。在具体目标#1中，我们将描述导致种内竞争的广泛作用的肺气球菌素的特征。具体地说，我们将1)鉴定广泛作用的肺炎球菌素及其免疫基础，2)确定肺炎球菌素的贡献及其对临床分离株之间竞争的免疫力，以及3)测试这些肺炎球菌素是否可用于减少肺炎球菌的定植。我们还表明，表达相同的肺炎蛋白等位基因并且缺乏直接细菌-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，在特定的目标#2中，我们将确定宿主的先天免疫反应和对这些反应的不同细菌抵抗力是否有助于在定殖期内的种内竞争。我们将集中讨论肺炎球菌清除的主要机制，包括补体和吞噬细胞；以及主要的毒力因素和抵抗清除的决定因素，胶囊型，以确定它们在竞争中的作用。定义这两种非互斥的竞争机制，包括由竞争肺炎球菌或由宿主阐述抗肺炎球菌因子，将为为什么某些肺炎球菌菌株或类型占优势提供分子解释。公共卫生相关性：最近引入的儿童肺炎链球菌疫苗接种改变了导致疾病的菌株的谱，并揭示了竞争平衡对该物种的生态和疾病预防的重要性。这个项目的重点是定义这种领先的人类病原体是如何发生竞争的。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情况，以及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.