Identifying polyamine dependent mechanisms in pneumococcal pneumonia

确定肺炎球菌肺炎的多胺依赖性机制

• 批准号: 8743219
• 负责人: Bindu Nanduri
• 金额: $ 23.8万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8743219
• 关键词: Acute-Phase Proteins; Anabolism; Antibiotic Resistance; Antibiotics; Bacterial Genes; Candidate Disease Gene; Centers of Research Excellence; Chronic Bronchitis; Communicable Diseases; Communities; Data; Dependence; Environment; Financial compensation; Future; Gene Expression; Genes; Genetic; Genomics; Goals; Growth; Hospitalization; Human; Immune; Immune response; Immune system; Immunization; In Vitro; Infection; Inflammation; Intervention; Investigation; Knowledge; Light; Lower respiratory tract structure; Lung; Measures; Meningitis; Metabolic; Metabolism; Methodology; Modeling; Molecular; Mus; Operon; Otitis Media; Pathogenesis; Pathway Analysis; Pathway interactions; Physiology; Pneumococcal Infections; Pneumococcal Pneumonia; Pneumonia; Polyamines; Proteins; Proteomics; Public Health; Receptor Signaling; Reporting; Resistance; Role; Serotyping; Signal Pathway; Sinusitis; Streptococcus pneumoniae; Structure of parenchyma of lung; Testing; Toll-like receptors; Transmission Electron Microscopy; United States; Vaccines; Virulence; Virulence Factors; Work; antimicrobial; attenuation; base; capsule; design; extracellular; in vivo; macrophage; mouse model; neutrophil; new therapeutic target; novel therapeutics; novel vaccines; pathogen; prophylactic; therapeutic target; transcriptome sequencing; vaccine candidate; vaccine development

Serotype variability, genomic plasticity and increasing antibiotic resistance of S. pneumoniae, pose considerable challenges for designing intervention strategies for this global public health concern. There is a need for the identification as well as characterization of novel vaccine candidates for effective immunization against pneumococcus, as the available vaccines are not effective against all serotypes. Polyamines are ubiquitous small cationic molecules necessary for pneumococcal growth and virulence. Therefore, intracellular polyamine levels are tightly regulated, thus making polyamine transport mechanisms a highly attractive focus for investigation on pathogenesis and immune responses. Our preliminary results indicate that impaired polyamine transport causes attenuation of pneumonia in mouse models. However, the pathogen-host interactions responsible for this attenuation are yet to be characterized. Our central hypothesis is that attenuation in pneumococcal pneumonia by impaired pneumococcal polyamine transport is due to the reduced virulence factor gene expression and/or reduced resistance to host innate immune responses. We will test this hypothesis by conducting the following specific aims. Specific aims: 1-identify polyamine responsive pneumococcal genes and pathways by comparing gene expression of wild type and ApotABCD S. pneumoniae (a strain with genetic deletion of polyamine transport operon) in a mouse model of pneumonia ; 2-determine the host innate immune responses to polyamine deficient pneumococcus by measuring the expression of antimicrobial proteins, acute phase proteins, opsonophagocytosis by macrophages and neutrophils, and host signaling pathways and functions including Toll-like receptor signaling, using proteomics. Successful completion ofthe proposed studies will identify the pneumococcal molecular mechanisms responsive to polyamine transport as well as specific host innate immune responses. Project results will shed light on the role of polyamines in infectious diseases in general for the identification of unique intra and extracellular targets for design of novel vaccines or therapeutics in future.

血清型变异性，基因组可塑性和肺炎链球菌的抗生素耐药性的增加，在为这一全球公共卫生问题设计干预策略方面构成了巨大的挑战。需要鉴定和表征新型候选疫苗以对肺炎球菌进行有效免疫，因为可用的疫苗对所有血清型都不有效。多胺是 无处不在的小阳离子分子是肺炎球菌生长和毒力所必需的。因此，细胞内多胺水平受到严格调节，从而使多胺转运机制成为研究发病机理和免疫反应的高度吸引人的重点。我们的初步结果表明，多胺转运受损会导致小鼠模型中肺炎的衰减。然而，导致这种衰减的病原体宿主相互作用尚未表征。我们的中心 假设是，肺炎球菌多胺转运受损是由于毒力因子基因的表达降低和/或对宿主先天免疫反应的抗性降低，肺炎球菌的肺炎衰减是由于肺炎球菌的转运受损。我们将通过执行以下特定目标来检验这一假设。具体目的：通过比较小鼠模型中野生型和apotabcd链球菌的基因表达（多胺转运操纵子的遗传缺失），通过比较野生型和apotabcd链球菌的基因表达来识别多胺反应性肺炎球菌基因和途径 肺炎； 2次确定，宿主对多胺对多胺缺乏肺炎球菌的免疫反应，通过测量巨噬细胞和中性粒细胞的抗菌蛋白，急性相蛋白的表达，急性相蛋白，ops虫的胞毒性，以及宿主信号途径和功能，包括使用蛋白质组学，包括Toll-like受体信号传导。拟议的研究的成功完成将确定对多胺转运的肺炎球菌分子机制以及特定的宿主先天免疫反应。 项目结果将揭示多胺在传染病中的作用，从而确定未来新型疫苗或治疗剂的独特内部和细胞外靶标。