Pneumococcal pathogenesis in sickle cell disease

镰状细胞病的肺炎球菌发病机制

基本信息

批准号：
9171341
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
项目类别：
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/9171341
关键词：
Address Antibiotic Resistance Automobile Driving Bacterial Infections Biological Models Biology Childhood Clinical Code Collection Complement Coupled Data Disease 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 Pathogenicity Pathway interactions Patients Penicillins Physiology Pneumococcal Colonization Pneumococcal Infections Pneumonia Population Predisposing Factor 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 high risk population mortality mutant novel novel therapeutics pathogen patient population peer permissiveness pressure prevent public health relevance tool vaccine candidate

项目摘要

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.