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差距，尤其是在高层人群中承受着发病率和死亡率不成比例的高级个人。尽管主要是血液学疾病，但最常见的镰状细胞病（SCD）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），表现为暴发型败血症。该宿主经历致命性肺炎球菌感染的可能性高400倍。尽管疫苗接种和青霉素预防，但SCD患者仍然存在肺炎球菌定植和侵袭性肺炎球菌疾病。长期目标是了解使SCD患者易于感染风险的细菌和宿主因素，并利用这种知识来开发针对这一高风险组量身定制的新型疗法。在此特定应用中的目标是遗传工具的应用，即转座子诱变和测序，以及SCD鼠系统在SCD的背景下精确定义了肺炎球菌发病机理。中心假设是可以利用肺炎球菌遗传学，以更精确地定义改变宿主中遇到的选择性压力，这反映了驱动增强感染风险的独特宿主生理学。在初步数据的指导下，将通过追求三个具体目的来检验该假设：1）在定植期间定义肺炎球菌基因在差异选择性压力下，SCD中的肺炎和肺炎，2）确定在不及时的coce coce coce coce coce coce coce coce and ofter coce coce coce and inty coce coce coce and ofter cole core Genome Intery Intery Intery Intery Intery Intneome Intneome Intneome Intneome Intneom cocococal intery Intery interiention的基础上。 SCD主机使宿主更允许侵入性肺炎球菌疾病。这些研究将通过利用SCD患者对肺炎球菌分离株的广泛基因组分析的数据来缩小当前知识的显着差距，并使用TN-SEQ对基因对发病机理进行建模和基因对发病机理的贡献，从而使在临床相关设置的SCD中研究了SCD疾病的各个方面。该研究提出，最近开发的遗传工具的应用来解决有关侵入性肺炎球菌疾病与SCD及其健康同龄人之间如何从细菌和宿主观点之间差异的基本问题。了解在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剂，以预防和治疗细菌感染以及这些修改后的策略应包含的内容。通过增加对SCD人群中侵袭性肺炎球菌疾病的了解，这些结果将对人类健康产生重要的积极影响，从而揭示了尽管有预防的预防，揭示了致命感染风险增加的因素，并确定了缓解感染严重程度的潜在目标途径。