Bacterial and host factors in pneumococcal competition

项目摘要 微生物在宿主表面上的建立和持久性将取决于它的能力， 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，有时会带来不希望的结果。 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，用非疫苗血清型替代的日益严重的问题表明， 疫苗已经减少了抑制这些细胞的竞争选择压力， 以前不太常见的血清型。因此，临床经验表明， 物种内的竞争，需要更好地了解影响它的因素 以维持或改进在其他方面成功的预防战略。的机制 这种种内竞争的基础可能是肺炎球菌 细菌素（细菌素）。这些由blp位点表达的小的抗菌肽 靶向不产生同源免疫蛋白的相同物种的成员。在 在小鼠定殖模型中，双链菌素决定了两个 分离株我们已经鉴定了表达广泛活性的抑制所有其他 肺炎球菌测试在具体目标#1中，我们将描述广泛作用的阿托莫西汀 促进种内竞争的因素。具体来说，我们将1）确定广泛的作用 免疫原性和对这些免疫原性的基础，2）确定的贡献 大肠杆菌素及其对临床分离株之间竞争的免疫力，以及3）测试这些 可使用氯霉素来减少肺炎球菌的定植。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，宿主因素也可以 决定了竞争的结果。因此，在具体目标#2中，我们将确定主机是否 先天免疫应答和细菌对这些应答的不同抗性有助于 殖民过程中的种内竞争。我们将重点关注的主要机制， 肺炎球菌清除，涉及补体和吞噬细胞;和主要毒力因子 和抗性决定因子的清除、荚膜类型，以确定它们在竞争中的作用。 界定这两种不相互排斥的竞争机制， 竞争性肺炎球菌或宿主产生的抗肺炎球菌因子， 解释为什么一些肺炎球菌菌株或类型盛行。

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.