Bacterial and host factors in pneumococcal competition

项目总结 微生物在宿主表面的建立和存留将取决于它的能力 与其他物种以及同一物种的成员竞争。操纵，例如 抗生素和疫苗，改变了这些关系的动态，有时与不受欢迎的 后果。肺炎链球菌结合疫苗的研究进展 通过包括的血清型的这种主要病原体降低了携带和疾病的负担。 然而，用非疫苗血清型替换的问题日益严重，这表明 疫苗已经减少了一直抑制这些的竞争选择压力。 以前不太常见的血清型。因此，临床经验揭示了这一重要性。 该物种的种内竞争以及更好地了解影响它的因素的必要性 以维持或改进原本成功的预防战略。一种机制，可以 可能是这种种内竞争的基础是肺炎球菌的阐述 细菌素(气球菌素)。这些由BLP基因座表达的小分子抗菌肽 以不产生同源免疫蛋白的同一物种的成员为目标。在 小鼠的定植模型，气球菌类决定了两种动物之间竞争的结果 分离株。我们已经确定了表达广泛活性的肺气球菌素的分离株，这些菌株抑制所有其他 肺炎球菌检测。在具体目标#1中，我们将描述广泛作用的肺气球菌素 这导致了种内竞争。具体地说，我们将1)确定广泛的代理 肺气球菌素及其免疫基础，2)确定 肺炎衣原体及其对临床分离株之间竞争的免疫力，以及3)测试这些 肺炎链球菌素可用于减少肺炎球菌的定植。我们还表明， 表达相同肺炎蛋白等位基因且缺乏直接抑菌作用的菌株 仍然能够在活体内竞争。因此，初步数据表明，宿主因素也可以 决定竞争的结果。因此，在具体目标#2中，我们将确定主机是否 先天免疫反应和细菌对这些反应的不同抵抗力有助于 在殖民期间的种内竞争。我们将重点关注以下主要机制： 肺炎球菌清除，包括补体和吞噬细胞；以及主要毒力因素 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。 界定这两种非互斥的竞争机制，涉及详细说明 通过竞争肺炎球菌或由宿主提供的抗肺炎球菌因子，将提供一种分子 解释为什么某些肺炎球菌菌株或类型流行。

PROJECT SUMMARY 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.