Pneumococcal pathogenesis in sickle cell disease

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不成比例的高危个体中。虽然主要是一种血液疾病，但镰状细胞病（SCD）最常见的并发症之一是严重的细菌感染，特别是肺炎链球菌（肺炎球菌），表现为暴发性败血症。这种宿主比健康宿主更有可能经历致命的肺炎球菌感染。尽管接种疫苗和青霉素预防，肺炎球菌定植和侵袭性肺炎球菌疾病仍然存在于SCD患者中。长期目标是了解导致SCD患者感染风险更大的细菌和宿主因素，并利用这些知识开发针对这一高危群体的新型疗法。该特定应用的目的是应用两种遗传工具，即转座子诱变和测序，以及SCD鼠系统，以精确定义SCD背景下的肺炎球菌发病机制。核心假设是，可以利用肺炎球菌遗传学来更精确地定义在改变的宿主中遇到的选择压力，反映了驱动感染风险增加的独特宿主生理学。在初步数据的指导下，将通过追求三个具体目标来检验这一假设：1）在SCD中定殖和肺炎期间在不同选择压力下定义肺炎球菌基因，2）确定SCD中非典型荚膜类型和改变的核心基因组肺炎球菌变体保持侵袭性的潜在机制，和3）在SCD宿主中建立代谢因子，使宿主对侵袭性肺炎球菌疾病更宽容。这些研究将通过利用来自SCD患者的肺炎球菌分离株的广泛基因组分析的数据以及使用Tn-seq对感染和基因对发病机制的贡献进行建模的能力来弥补当前知识的重大差距，从而为在临床相关环境中研究SCD背景下肺炎球菌疾病的各个方面提供了独特的机会。这项研究使最近开发的遗传工具的应用能够解决有关侵袭性肺炎球菌疾病如何从细菌和宿主的角度与SCD患者及其健康同龄人之间的差异的基本问题。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，以及这些改良策略应涵盖的内容。这些结果将对人类健康产生重要的积极影响，通过增加对SCD人群中侵袭性肺炎球菌疾病的了解，揭示尽管目前的预防措施，致命感染风险增加的潜在因素，并确定潜在的靶向途径，以减轻感染的严重程度。

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.