Early Events in Pneumococcal Colonization

肺炎球菌定植的早期事件

基本信息

批准号：
8630673
负责人：
Jeffrey Neal Weiser
金额：
$ 39.47万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8630673
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 Infection Inflammation Inflammatory Response Influenza Integration Host Factors Laboratory Study Mediating Metabolism Microbe Modeling Morbidity - disease rate Mucositis Mucous body substance Mus 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 Inflammation Upper respiratory tract Vaccinated Vaccines Viral Virus Diseases 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

项目摘要

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.

项目概要急性呼吸道感染（ARI）仍然是全世界发病率和死亡率的主要来源。流行病学证据和针对 ARI 的三种疫苗的经验表明获得定植是最终进展为疾病、传播和传播的关键事件预防。该应用程序的重点是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（URT）。肺炎链球菌是 ARI 的主要原因，特别是在病毒共存的情况下感染，将用于检查导致感染的微生物和宿主因素。初步数据表明，在沿线建立稳定的细菌种群之前发现上皮表面肺炎球菌被困在腔粘液中。我们将使用鼠标用于检查肺炎球菌与粘液相互作用的运输模型以及这一最早的事件是如何发生的决定定植的成功（目标#1）并受到炎症（目标#2）和免疫的影响（目标#3）。初步数据支持在 Aim#1 中测试的机制，其中肺炎球菌操纵糖使其分解并利用粘多糖它的增殖、适应和逃避粘液截留。我们建议这些活动需要发展足够密度和持续时间的殖民化，以允许传播。额外的初步数据表明 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协同作用的作用甲型流感感染对粘液产生的影响及其在增强早期事件中的作用殖民化将在目标#2 中进行检查。在目标 #3 中，我们将检查 IgG 的贡献血清池阻断采集和传输的作用，并确定其机制抗体介导的对定植早期事件的抑制。因此，该应用程序解决对发病机制具有广泛意义的基本过程 - i) 宿主获取微生物，ii) 在该宿主中增殖，iii）传播到新宿主，iv）炎症的影响微生物的生态位，以及 v) 免疫宿主中这些参数的调节。