Early Events in Pneumococcal Colonization

描述（由申请人提供）：急性呼吸道感染（ARI）仍然是世界范围内发病率和死亡率的主要来源。流行病学证据和针对三种急性呼吸道感染的疫苗的经验表明，获得定植是最终发展为疾病、传播和预防的关键事件。本应用的重点是了解宿主-病原体相互作用中的第一个事件，即在上呼吸道（URT）粘膜表面建立定植。肺炎链球菌是引起急性呼吸道感染的主要原因，特别是在病毒共感染的情况下，将用于检查导致感染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。我们将使用小鼠携带模型来检查肺炎球菌与粘液的相互作用，以及这种最早的事件如何决定定植的成功（目标1），并受炎症（目标2）和免疫（目标3）的影响。初步数据支持在Aim#1中测试的一种机制，即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、适应和逃避粘液夹带。我们认为，这些事件是发展足够密度和持续时间的殖民化以允许传播所必需的。额外的初步数据表明，上呼吸道炎症促进而不是抑制肺炎球菌的定植。肺炎球菌诱导的炎症和甲型流感共感染对粘液产生的作用及其在促进定植早期事件中的作用将在Aim#2中进行研究。在Aim#3中，我们将检查血清池中IgG在阻断获取和传播中的作用，并确定抗体介导的定殖早期事件抑制机制。因此，该应用程序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)宿主增殖，iii)传播到新宿主，iv)微生物生态位炎症的影响，以及v)这些参数在免疫宿主中的调节。

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.