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差距，特别是在患有不成比例的发病率和死亡率负担的高危个体中。虽然镰状细胞病（SCD）主要是一种血液系统疾病，但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），其表现为暴发性败血症。这种宿主比健康宿主更容易感染致命的肺炎球菌。尽管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仍然存在于SCD患者。长期目标是了解使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。在这个特殊的应用中，目的是应用遗传工具，即转座子突变和测序，以及SCD小鼠系统来精确定义SCD背景下肺炎球菌的发病机制。核心假设是，肺炎球菌遗传学可以被用来更精确地定义在改变的宿主中遇到的选择压力，反映出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，这一假设将通过追求三个特定目标来验证：1)确定在SCD定植和肺炎期间不同选择压力下的肺炎球菌基因；2)确定SCD中非典型荚膜类型和核心基因组改变的肺炎球菌变异体保持侵袭性的机制；3)确定SCD宿主的代谢因子，使宿主更容易发生侵袭性肺炎球菌疾病。这些研究将通过利用来自SCD患者的肺炎球菌分离物的广泛基因组分析数据，以及利用n-seq对感染和基因对发病机制的贡献进行建模的能力，填补当前知识的重大空白，从而为在临床相关环境中调查SCD背景下肺炎球菌疾病的各个方面提供了独特的机会。提出的研究使最近开发的遗传工具的应用能够从细菌和宿主的角度解决关于SCD患者与健康同伴之间侵袭性肺炎球菌疾病的差异的基本问题。了解SCD背景下宿主-病原体相互作用的差异将确定这一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该包括什么。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，揭示尽管目前采取了预防措施，但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.