Dysregulation of the inflammatory response by Francisella tularensis

土拉弗朗西斯菌引起的炎症反应失调

• 批准号: 10620249
• 负责人: Lee-Ann H Allen
• 金额: --
• 依托单位: HARRY S. TRUMAN MEMORIAL VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2023-04-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620249
• 关键词: Affect; Apoptosis; Apoptosis Regulation Gene; Arthritis; Atherosclerosis; BCL2/Adenovirus E1B 19kd Interacting Protein 3-Like; BIRC4 gene; Bacteremia; Caspase; Cells; Cessation of life; Circulation; Colitis; Communicable Diseases; Conditioned Culture Media; Data; Defect; Development; Disease; Drug Utilization; Enzyme Induction; Experimental Designs; Francisella tularensis; Genes; Genetic Polymorphism; Glycolysis; Glycolysis Induction; Growth; Health; Human; Infection; Inflammation; Inflammatory; Inflammatory Response; Inhibition of Apoptosis; Intervention; Kinetics; Leukocytes; Ligands; Link; Lipoproteins; Longevity; Lupus; Lyme Disease; MAP Kinase Gene; Macrophage; Macrophage Activation; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Microbe; Mitochondria; Neisseria gonorrhoeae; Nutrient; Organelles; Outcome; Pathogenesis; Pathway interactions; Phagocytes; Pharmaceutical Preparations; Play; Process; Proteins; Pyelonephritis; Regulation; Research; Resolution; Role; Sepsis; Severities; Signal Transduction; Single Nucleotide Polymorphism; Symptoms; TLR1 gene; TLR2 gene; Therapeutic; Therapeutic Intervention; Tissues; Tuberculosis; Tularemia; Up-Regulation; Veterans; adaptive immune response; differential expression; drug testing; enzyme pathway; hexokinase; improved; innovation; insight; neutrophil; p38 Mitogen Activated Protein Kinase; pathogen; pathogenic bacteria; receptor; synergism; targeted treatment; transcriptome

Tularemia is a potentially fatal disease and the causative agent, Francisella tularensis (Ft), is one of few bacterial pathogens that can infect both neutrophils (polymorphonuclear leukocytes, PMNs) and macrophages. Notably, macrophages and neutrophils appear to play distinctly different roles in tularemia pathogenesis, with macrophages acting as major vehicles for bacterial growth and dissemination, and PMNs playing a central role in host tissue destruction. Neutrophils are short lived, and unlike other leukocytes are preprogrammed to undergo apoptosis 24 h after release into the circulation. Tight spatial and temporal control of this process is critical for elimination of infection and resolution of inflammation, and for this reason defects in PMN turnover exemplify a dysregulated and ineffective inflammatory response that promotes tissue destruction and disease. In keeping with this, we discovered that Ft inhibits human neutrophil apoptosis and markedly prolongs cell lifespan, and demonstrated that this is achieved via effects on the intrinsic and extrinsic apoptosis pathways, as well as changes in the neutrophil transcriptome that include significant differential expression of 365 unique genes linked to apoptosis and cell fate. Nevertheless, how cell lifespan is prolonged is only partially understood. Herein, we propose groundbreaking studies based on our discovery of neutrophil metabolic reprogramming as a new mechanism for apoptosis inhibition. Our proposed studies are supported by extensive preliminary data, and are highly innovative, as integrated manipulation of glycolysis and organelle function has not been previously documented as a mechanism for regulation of PMN lifespan during infection. Potential effects of these changes on bacterial growth and the influence of PMN metabolites on macrophage polarization will also be determined. In addition, we recently identified bacterial lipoproteins (BLPs) as active factors in Ft conditioned medium (CM) that extend PMN lifespan via a mechanism that is dependent on a common single nucleotide polymorphism (SNP) in human TLR1 (rs5743618, T1805G) that significantly influences the severity and lethality of sepsis as well as the outcomes of many infectious and inflammatory diseases, including but not limited to tuberculosis, pyelonephritis, atherosclerosis, arthritis, lupus, colitis, and cancer. Elucidating the mechanism(s) of BLP and TLR2/1-driven apoptosis inhibition is a second objective of this study. Our experimental design will also utilize drugs that specifically target HIF-1 and TLR2, mitophagy, glycolysis or other relevant signaling intermediates to identify points for therapeutic intervention that are expected to be relevant to many diseases that affect Veterans. Our specific aims are: 1) To elucidate the mechanisms and functional consequences of neutrophil metabolic reprogramming. 2) To elucidate the mechanisms of BLP and TLR2/1-mediated apoptosis inhibition and potential for theraputic intervention.

Tularemia是一种潜在的致命疾病，病因剂Francisella tularensis（ft）是少数 可以感染嗜中性粒细胞（多形核白细胞，PMN）和巨噬细胞的细菌病原体。 值得注意的是，巨噬细胞和中性粒细胞似乎在图拉米亚发病机理中起着明显不同的作用，并且 巨噬细胞充当细菌生长和传播的主要车辆，PMN发挥了核心作用 在宿主组织破坏中。嗜中性粒细胞短暂，与其他白细胞不同，将 释放到循环后24小时进行凋亡。紧密的空间和临时控制此过程是 对于感染和感染的分辨率至关重要，因此，PMN周转率缺陷 体现了促进组织破坏和疾病的失调和无效的炎症反应。 因此，我们发现FT抑制了人类嗜中性粒细胞凋亡，并明显延长细胞 寿命，并证明这是通过对内在和外在凋亡途径的影响来实现的 以及中性粒细胞转录组的变化，包括365的显着差异表达 与细胞凋亡和细胞命运有关的基因。然而，细胞寿命如何延长仅部分是部分 理解齿。本文中，我们根据发现中性粒细胞代谢的开创性研究 重新编程是凋亡抑制的新机制。我们提出的研究得到了广泛的支持 初步数据，并且具有高度创新性，因为糖酵解和细胞器功能的综合操纵具有 以前未被记录为调节感染过程中PMN寿命的机制。潜在的 这些变化对细菌生长的影响以及PMN代谢物对巨噬细胞极化的影响 也将确定。此外，我们最近将脂蛋白细菌（BLP）确定为ft中的活性因子 条件培养基（cm），该培养基通过一种取决于常见单一的机制来延长PMN寿命 人TLR1（rs5743618，T1805G）中的核苷酸多态性（SNP）显着影响严重性 败血症以及许多传染病和炎症性疾病的结果，包括但不是 仅限于结核病，肾上腺炎，动脉粥样硬化，关节炎，狼疮，结肠炎和癌症。阐明 BLP和TLR2/1驱动的凋亡抑制的机理是本研究的第二个目标。我们的 实验设计还将利用专门针对HIF-1和TLR2，线粒能，糖酵解或 其他相关信号传导中间体，以识别预期的热干预点 与许多影响退伍军人的疾病有关。我们的具体目的是：1）阐明机制和 中性粒细胞代谢重编程的功能后果。 2）阐明BLP和 TLR2/1介导的凋亡抑制和热干预的潜力。