Early Events in Pneumococcal Colonization

肺炎球菌定植的早期事件

• 批准号: 9185923
• 负责人: Jeffrey Neal Weiser
• 金额: $ 42.38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9185923
• 关键词: Acute respiratory infection; Address; Adherence; Affect; Agglutination; Antibodies; Bacteria; Biological Assay; Biology; Blocking Antibodies; Carrier State; Childhood; Data; Development; Epidemiology; Epithelial; Event; Exoglycosidases; Glycosaminoglycans; Haemophilus influenzae type b bacteria; Herd Immunity; Human; Immune; Immune response; Immunity; Immunoglobulin G; Inflammation; Inflammatory Response; Influenza A virus; Integration Host Factors; Laboratory Study; Mediating; Metabolism; Microbe; Morbidity - disease rate; Mucositis; Mucous body substance; Nasopharynx; Neisseria meningitidis; Nose; Nutrient; Pathogenesis; Persons; Pneumococcal Colonization; Pneumococcal Infections; Polysaccharides; Population; Prevention; Process; Production; Respiratory System; Respiratory tract structure; Role; Serum; Sialic Acids; Source; Streptococcus pneumoniae; Surface; Testing; Time; Upper respiratory tract; Vaccinated; Vaccines; Viral; Virus Diseases; co-infection; density; disease transmission; disorder prevention; experience; inhibiting antibody; microbial disease; microbial host; mortality; mouse model; pathogen; public health relevance; success; sugar; transmission process; vaccine effectiveness

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.

描述（由申请人提供）：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。流行病学证据和针对 ARI 的三种疫苗的经验表明，定植的获得是疾病最终进展、传播和预防的关键事件。该应用的重点是了解宿主与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。初步数据表明，在沿着上皮表面建立稳定的细菌群之前，发现肺炎球菌被困在腔粘液中。我们将使用小鼠运输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 Aim#1 中待测试的机制，即肺炎球菌操纵糖的能力使其能够分解并利用粘多糖进行增殖、适应并逃脱粘液截留。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定殖所必需的。其他初步数据表明，URT 炎症会促进而不是抑制肺炎球菌定植。肺炎球菌引起的炎症和甲型流感合并感染对粘液产生的作用及其在增强定植早期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 IgG 在阻断获取和传播中的作用，并确定抗体介导的对定植早期事件的抑制机制。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)在该宿主中增殖，iii)传播到新宿主，iv)炎症对微生物生态位的影响，以及v) 在免疫宿主中调节这些参数。