Early Events in Pneumococcal Colonization

描述(申请人提供)：急性呼吸道感染(ARI)仍然是全球发病率和死亡率的主要来源。针对ARIS的三种疫苗的流行病学证据和经验表明，获得殖民是最终发展为疾病、传播和预防的关键事件。这项应用侧重于了解宿主和病原体相互作用的第一个事件，即在上呼吸道(URT)粘膜表面建立定植。肺炎链球菌是ARI的主要原因，特别是在病毒合并感染的情况下，将用于检查促成获得的微生物和宿主因素。初步数据显示，在沿着上皮表面建立稳定的细菌种群之前，发现肺炎球菌被困在管腔粘液中。我们将使用携带的小鼠模型来检查肺炎球菌与粘液的相互作用，以及这一最早的事件如何决定定植成功(目标1)，以及如何受到炎症(目标2)和免疫(目标3)的影响。初步数据支持在AIM#1中测试一种机制，根据该机制，肺炎球菌操纵糖的能力使其能够分解和利用粘多糖进行增殖、适应和逃脱粘液捕获。我们认为，这些事件是发展足够密度和持续时间以允许传播的殖民所必需的。额外的初步数据表明，URT炎症促进而不是抑制肺炎球菌的定植。肺炎球菌引起的炎症和与甲型流感混合感染对粘液产生的作用及其在促进早期定植事件中的作用将在目标2中进行研究。在目标3中，我们将检查血清池中的免疫球蛋白在阻断获取和传播方面的作用，并确定抗体介导的抑制定植早期事件的机制。因此，本申请解决了对发病机制具有广泛意义的基本过程-i)宿主获得微生物，ii)宿主中的增殖，iii)向新宿主的传播，iv)微生物生态位中炎症的影响，以及v)免疫宿主中这些参数的调节。

DESCRIPTION (provided by applicant): 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) transmisson 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.