Pneumococcal pathogenesis in sickle cell disease

镰状细胞病的肺炎球菌发病机制

• 批准号: 8963424
• 负责人: Jason W. Rosch
• 金额: $ 44.5万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8963424
• 关键词: Address; Antibiotic Resistance; Automobile Driving; Bacterial Infections; Biological Models; Biology; Childhood; Clinical; Code; Collection; Complement; Coupled; Data; Disease; Disease model; Environment; Evaluation; Experimental Models; Functional disorder; General Population; Genes; Genetic; Genome; Genomics; Goals; Health; Hematological Disease; Human; Individual; Infection; Integration Host Factors; Intervention; Iron; Knowledge; Link; Metabolic; Mission; Modeling; Morbidity - disease rate; Mus; Mutagenesis; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Disease; Pathogenesis; Pathway interactions; Patients; Penicillins; Physiology; Pneumococcal Colonization; Pneumococcal Infections; Pneumonia; Population; Predisposition; Prophylactic treatment; Proteins; Public Health; Research; Risk; Sepsis; Serotyping; Severities; Sickle Cell Anemia; Streptococcus pneumoniae; System; Testing; Therapeutic; Time; United States National Institutes of Health; Vaccination; Vaccines; Variant; Virulence; capsule; clinically relevant; comparative; defined contribution; experience; falls; genetic selection; genomic data; high risk; mortality; mutant; novel; novel therapeutics; pathogen; patient population; peer; pressure; prevent; tool; vaccine candidate

DESCRIPTION (provided by applicant): There is a fundamental gap in our understanding of how unique aspects of host physiology influences infection susceptibility, particularly in high-ris individuals who carry a disproportionate burden of morbidity and mortality. Though primarily a hematological disorder, one of the most frequent complications of sickle cell disease (SCD) is severe bacterial infection, particularly with Streptococcus pneumoniae (pneumococcus), which manifests as a fulminant sepsis. This host is 400 times more likely to experience lethal pneumococcal infection than healthy hosts. Despite both vaccination and penicillin prophylaxis, pneumococcal colonization and invasive pneumococcal disease persists in SCD patients. The long-term goal is to understand the bacterial and host factors that predispose SCD patients to greater infection risk and to leverage this knowledge to develop novel therapies tailored to this high-risk group. The objective in this particular application is the application of both genetic tools, namely transposon mutagenesis and sequencing, and the SCD murine system to precisely define pneumococcal pathogenesis in the context of SCD. The central hypothesis is that pneumococcal genetics can be exploited to more precisely define the selective pressures encountered in an altered host, reflecting the unique host physiology that drives heightened infection risk. Guided by preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Define the pneumococcal genes under differential selective pressure during colonization and pneumonia in SCD, 2) Ascertain the mechanisms underlying the retention of invasiveness by both atypical capsular types and altered core genome pneumococcal variants in SCD, and 3) Establish the metabolic factors in the SCD host rendering the host more permissive to invasive pneumococcal disease. These studies will close a significant gap in current knowledge by leveraging data from extensive genomic analysis of pneumococcal isolates from SCD patients and the capacity to model both infection and the contribution of genes to pathogenesis using Tn-seq, allowing a unique opportunity to investigate aspects of pneumococcal disease in the context of SCD in a clinically relevant setting. The research proposed enables the application of recently developed genetic tools to address fundamental questions about how invasive pneumococcal disease differs between those with SCD and their healthy peers from both the bacterial and host perspectives. Understanding the differences of host-pathogen interactions in the context of SCD will establish that this population requires distinct vaccine strategies and therapeutics to both prevent and treat bacterial infections and what these modified strategies should encompass. These results will have an important positive impact on human health by increasing understanding of invasive pneumococcal disease in the SCD population, revealing the factors underlying the increased risk of fatal infection despite current prophylaxis, and identifying potentially targetable pathways to mitigate the severity of infection.

描述（由申请人提供）：我们对宿主生理学的独特方面如何影响感染易感性的理解存在根本性差距，特别是在发病率和死亡率负担过重的高风险个体中。虽然主要是一种血液系统疾病，但镰状细胞病 (SCD) 最常见的并发症之一是严重的细菌感染，尤其是肺炎链球菌（肺炎球菌）感染，表现为暴发性败血症。该宿主遭受致命肺炎球菌感染的可能性是健康宿主的 400 倍。尽管进行了疫苗接种和青霉素预防，肺炎球菌定植和侵袭性肺炎球菌疾病在 SCD 患者中仍然存在。长期目标是了解导致 SCD 患者感染风险增加的细菌和宿主因素，并利用这些知识开发针对这一高危人群的新疗法。这一特定应用的目标是应用遗传工具（即转座子诱变和测序）和 SCD 小鼠系统来精确定义 SCD 背景下的肺炎球菌发病机制。中心假设是，可以利用肺炎球菌遗传学来更精确地定义改变的宿主所遇到的选择压力，反映导致感染风险升高的独特宿主生理学。在初步数据的指导下，该假设将通过追求三个具体目标进行检验：1）定义定植和 SCD 肺炎期间不同选择压力下的肺炎球菌基因，2）确定非典型荚膜类型和改变的肺炎球菌保留侵袭性的机制SCD 中的核心基因组肺炎球菌变异，以及 3) 在 SCD 宿主中建立代谢因素，使宿主更容易患侵袭性肺炎球菌疾病。这些研究将利用对 SCD 患者肺炎球菌分离株进行广泛基因组分析的数据，以及使用 Tn-seq 模拟感染和基因对发病机制的贡献的能力，从而缩小当前知识的重大差距，从而提供独特的机会来研究 SCD 患者肺炎球菌分离株的各个方面。临床相关环境中 SCD 背景下的肺炎球菌疾病。拟议的研究能够应用最近开发的遗传工具来解决从细菌和宿主角度来看，SCD 患者和健康人之间的侵袭性肺炎球菌疾病有何不同的基本问题。了解 SCD 背景下宿主-病原体相互作用的差异将确定该人群需要不同的疫苗策略和治疗方法来预防和治疗细菌感染，以及这些修改后的策略应涵盖哪些内容。这些结果将对人类健康产生重要的积极影响，增加对 SCD 人群侵袭性肺炎球菌疾病的了解，揭示尽管目前采取预防措施但致命感染风险增加的潜在因素，并确定减轻感染严重程度的潜在目标途径。