Early Events in Pneumococcal Colonization

项目摘要 急性呼吸道感染（ARI）仍然是全世界发病率和死亡率的主要来源。 针对阿里斯的三种疫苗的流行病学证据和经验表明， 获得定植是最终进展为疾病、传播和 预防 该应用程序侧重于了解宿主-病原体中的第一个事件 相互作用，在上呼吸道粘膜表面建立定植 （乌拉圭）。肺炎链球菌是ARI的主要病因，特别是在病毒性共感染的情况下， 感染，将被用来检查微生物和宿主因素有助于收购。 初步数据显示，在沿着 发现上皮表面肺炎球菌包埋在内腔粘液中。 我们将使用鼠标 一种携带模型，以检查肺炎球菌与粘液的相互作用，以及这种最早的事件 决定定植成功（目标#1），并受炎症（目标#2）和免疫力的影响 (Aim#3）。初步数据支持将在目标1中测试的一种机制， 肺炎球菌操纵糖使其分解并利用粘多糖， 其增殖、适应和逃避粘液截留。我们认为这些事件是 需要足够的密度和持续时间的殖民发展， 传输 额外的初步数据表明，URT炎症促进，而不是 抑制肺炎球菌定植。 肺炎球菌引起的炎症和协同作用的作用， 流感病毒A感染对粘液产生的影响及其在增强 将在目标#2中检查定殖。 在目标#3中，我们将检查IgG的贡献， 血清池在阻断获得和传递中的作用，并确定 抗体介导的对定植早期事件的抑制。 因此，本申请解决了 对发病机理具有广泛意义的基本过程- i）宿主获得微生物，ii） 在宿主中增殖，iii）传播到新宿主，iv）炎症在 微生物的生态位，和v）免疫宿主中这些参数的调节。

Project Summary Acute respiratory infection (ARI) remains a major source of morbidity and mortality worldwide. Epidemiologic evidence and experience with three vaccines targeting ARIs point to the acquisition of colonization as the key event in eventual progression to disease, transmission and prevention. This application focuses on understanding the first event in host-pathogen interaction, establishment of colonization on the mucosal surface of the upper respiratory tract (URT). Streptococcus pneumoniae, a leading cause of ARI particularly in the setting of viral co- infection, will be used to examine the microbial and host factors contributing to acquisition. Preliminary data show that prior to the establishment of a stable bacterial population along the epithelial surface pneumococci are found entrapped in lumenal mucus. We will use a mouse model of carriage to examine pneumococcal interaction with mucus and how this earliest event dictates success in colonization (Aim#1) and is affected by inflammation (Aim#2) and immunity (Aim#3). Preliminary data support a mechanism to be tested in Aim#1 whereby the ability of the pneumococcus to manipulate sugars allows it to breakdown and utilize mucopolysaccharides for its proliferation, adaptation and to escape mucus entrapment. We propose that these events are required for the development of colonization of sufficient density and duration to allow for transmission. Additional preliminary data suggest that URT inflammation promotes rather than inhibits pneumococcal colonization. The role of pneumococcal-induced inflammation and co- infection with influenza A on mucus production and their role in enhancing early events in colonization will be examined in Aim#2. In Aim#3 we will examine the contribution of IgG from the serum pool in blocking acquisition and transmission, and determine the mechanism for antibody-mediated inhibition of early events in colonization. Thus, this application addresses basic processes of broad significance to pathogenesis- i) acquisition of a microbe by a host, ii) proliferation in that host, iii) transmission to a new host, iv) the effect of inflammation in the microbe's niche, and v) the modulation of these parameters in an immune host.