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，将定植作为最终发展为疾病，传播和预防的关键事件。该应用的重点是理解宿主 - 病原体相互作用的第一个事件，在上呼吸道（URT）的粘膜表面上建立定殖。肺炎链球菌是ARI的主要原因，尤其是在病毒感染的环境中，将用于检查有助于获取的微生物和宿主因素。初步数据表明，在建立沿上皮表面肺炎球菌稳定的细菌种群之前，发现被夹在腔粘液中。我们将使用马车的小鼠模型来检查与粘液的肺炎球菌相互作用，以及该最早事件如何决定定植的成功（AIM＃1）并受炎症（AIM＃2）和免疫力的影响（AIM＃3）。初步数据支持在AIM＃1中进行测试的机制，在该机制中，肺炎球菌操纵糖的能力使其可以分解并利用粘多糖进行增殖，适应并避免粘液夹层。我们建议这些事件是开发足够密度和持续时间的定殖以进行传播所必需的。其他初步数据表明，URT炎症会促进而不是抑制肺炎球菌定殖。肺炎球菌引起的炎症和与流感A的共同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AIM＃2中进行检查。在AIM＃3中，我们将研究血清库中IgG在阻断采集和传播方面的贡献，并确定抗体介导的抑制早期事件在定植中的抑制机制。因此，该应用程序解决了对发病机理具有广泛意义的基本过程 - i）通过宿主获取微生物，ii）宿主的增殖，iii）将植物传播到新宿主，iv）iv）iv）微生物利基市场中炎症的效果，v）v）对这些免疫宿主中这些参数的调节。