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.

兔热病是一种潜在的致命疾病，其病原体土拉弗朗西斯菌 (Ft) 是少数几种致命疾病之一。 可以感染中性粒细胞（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兔热病发病机制中发挥着截然不同的作用， 巨噬细胞是细菌生长和传播的主要载体，PMN 发挥着核心作用 在宿主组织破坏中，中性粒细胞的寿命很短，并且与其他白细胞不同的是，它们被预先编程为 释放到循环中后 24 小时发生细胞凋亡，该过程的严格空间和时间控制是。 对于消除感染和消炎至关重要，因此中性粒细胞周转缺陷 例证了促进组织破坏和疾病的失调和无效的炎症反应。 与此相一致，我们发现 Ft 抑制人中性粒细胞凋亡并显着延长细胞凋亡时间。 寿命，并证明这是通过影响内在和外在细胞凋亡途径来实现的， 第365章 被人欺负了 然而，细胞寿命如何增殖只是部分的。 在此，我们基于中性粒细胞代谢的发现提出了开创性的研究。 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已经 此前尚未被证明是感染期间调节 PMN 寿命的机制。 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 此外，我们最近还确定了细菌脂蛋白（BLP）是 Ft 中的活性因子。 条件培养基（CM），通过依赖于共同单一的机制来延长中性粒细胞寿命 人 TLR1（rs5743618、T1805G）中的核苷酸多态性 (SNP) 显着影响严重程度 败血症的致死率以及许多传染病和炎症性疾病的结果，包括但不限于 仅限于结核病、肾盂肾炎、动脉粥样硬化、关节炎、狼疮、结肠炎和癌症。 BLP 和 TLR2/1 驱动的细胞凋亡抑制机制是本研究的第二个目标。 实验设计还将利用专门针对 HIF-1α 和 TLR2、线粒体自噬、糖酵解或 其他相关的信号传导中间体，以确定预期的治疗干预点 与影响退伍军人的许多疾病相关，我们的具体目标是：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 和的机制。 TLR2/1 介导的细胞凋亡抑制和治疗干预的潜力。