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: 9119122
• 负责人: Bindu Nanduri
• 金额: $ 23.37万
• 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/9119122
• 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.

肺炎链球菌的血清型变异性、基因组可塑性和抗生素耐药性的增加，为针对这一全球公共卫生问题设计干预策略提出了相当大的挑战。由于现有疫苗并非对所有血清型都有效，因此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。多胺是 肺炎球菌生长和毒力所必需的普遍存在的小阳离子分子。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发病机制和免疫反应研究的一个极具吸引力的焦点。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减弱。然而，导致这种减弱的病原体-宿主相互作用尚未得到表征。我们的中央 假设认为，肺炎球菌多胺转运受损导致肺炎球菌肺炎减弱是由于毒力因子基因表达减少和/或对宿主先天免疫反应的抵抗力降低。我们将通过实现以下具体目标来检验这一假设。具体目标： 1-通过比较小鼠模型中野生型和 ApotABCD 肺炎链球菌（一种多胺转运操纵子基因缺失的菌株）的基因表达，鉴定多胺反应性肺炎球菌基因和途径 肺炎； 2-通过使用蛋白质组学测量抗菌蛋白、急性期蛋白、巨噬细胞和中性粒细胞的调理吞噬作用以及包括Toll样受体信号传导在内的宿主信号传导途径和功能的表达，确定宿主对多胺缺乏型肺炎球菌的先天免疫反应。成功完成拟议的研究将确定肺炎球菌对多胺转运反应的分子机制以及特定宿主先天免疫反应。 项目结果将揭示多胺在传染病中的一般作用，以识别独特的细胞内和细胞外靶点，以便未来设计新型疫苗或疗法。