The Role of Eicosanoid-PPAR axis in Exacerbating Post-Influenza Staphylococcus aureus Super-infection

类花生酸-PPAR 轴在加剧流感后金黄色葡萄球菌双重感染中的作用

• 批准号: 10553714
• 负责人: Vincent Tam
• 金额: $ 39.5万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-21 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553714
• 关键词: Affect; Alveolar Macrophages; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Bacterial Infections; Cell Survival; Cell physiology; Cells; Cellularity; Cessation of life; Chemicals; Clinical; Complication; Disease; Disease Outcome; Eicosanoids; Electrospray Ionization; Failure; Fatty Acids; Gene Expression Profiling; Genetic; Genetic Models; Genetic Transcription; Goals; Homeostasis; Human; Immune; Immune response; Immune signaling; Immune system; Immunologics; Immunotherapeutic agent; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza; Investigation; Knockout Mice; Lipids; Lung; Macrophage; Mass Spectrum Analysis; Mediating; Metabolic Pathway; Metabolism; Modeling; Molecular; Mus; Nuclear Receptors; PPAR alpha; PPAR gamma; Patients; Peroxisome Proliferator-Activated Receptors; Phase; Physiological; Play; Pneumonia; Process; Production; Research; Resolution; Role; Sampling; Serum; Signal Transduction; Signaling Molecule; Spatial Distribution; Staphylococcus aureus; Staphylococcus aureus infection; System; Systems Biology; Time; Tissues; Viral Load result; Virus Diseases; Work; clinically relevant; cytokine release syndrome; eicosanoid metabolism; fatty acid metabolism; human disease; immunoregulation; improved; influenza infection; inhibitor; insight; lipid mediator; lipid metabolism; lipidomics; mass spectrometric imaging; microbial; mouse model; nano-string; new therapeutic target; novel therapeutic intervention; pathogen; pathogenic bacteria; recruit; response; secondary infection; severe COVID-19; superinfection; transcription factor

PROJECT SUMMARY/ABSTRACT Secondary bacterial infection following influenza (super-infection) can lead to cytokine storm (an overexuberant immune response) that often leads to pneumonia and death in patients. Our work focuses on the molecular mechanisms by which the immune system returns to homeostasis after microbial infections. Taking a holistic, systems approach, we investigated the inflammatory responses during a single (influenza or Staphylococcus aureus) and super-infection (influenza/S. aureus). We conducted transcriptional and lipidomic analyses in samples from a mouse super-infection model. Our lipidomic analysis was focused on eicosanoids because they play critical roles in inducing and resolving inflammation. When compared to single infections, we discovered an overproduction of a subset of eicosanoids during super-infection. These lipids (anti-inflammatory CYP450 lipid mediators, primarily DHET) can activate the nuclear receptors and transcription factors PPARa and PPARg. During influenza single infection, moderate induction of CYP lipids (primarily EET) during the resolution phase allows for appropriate anti-inflammatory responses to promote the return to homeostasis. We hypothesize that while EET promotes the physiological resolution of inflammation after microbial infections, DHET produced at an aberrant level during super-infection leads to the alteration in macrophage polarization and inhibition of bacterial clearance. The failure to control the bacterial pathogen amplifies the immune signals to recruit additional immune cells which eventually cause irreversible tissue damage. We will take the following approaches during single and super-infection to investigate the effects of the eicosanoid-PPAR axis on the inflammatory response. First, we will determine the effects of perturbing the eicosanoid-PPAR axis on the resolution or amplification of inflammation during single and super-infection. We will use chemical inhibitors in combination with genetic models to determine whether the animals will be protected from or succumb to disease during single and super- infection. We will determine the lipidomic profiles to assess the specific effects of the inhibitors have on the eicosanoid metabolism networks. We will also determine the bacterial/viral loads, cellularity, pathohistology, and targeted transcriptional profiling of macrophages. Second, we will determine the mechanism by which eicosanoid-activated PPARα/γ modulates immune signaling, macrophage polarization and immune metabolism in vitro. Macrophage polarization (classically or alternative activated) can amplify or resolve inflammatory responses. We will determine the potency of different CYP450 metabolites to activate PPARα/γ within mouse and primary human macrophages. We will determine how eicosanoids (CYP450 metabolites) affect the immune signaling, macrophage polarization, and lipid metabolism. Interestingly, While the induction of inflammation has been the subject of active investigation, the mechanisms underlying the resolution of inflammation have been elusive. By gaining insights into the resolution of inflammation during single and super-infection, we will develop novel therapeutic targets for infection- and immune-related human diseases.

项目摘要/摘要 流感后的继发性细菌感染(超级感染)可导致细胞因子风暴(过度兴奋) 免疫反应)，这往往会导致肺炎和病人死亡。我们的工作主要集中在分子上 微生物感染后免疫系统恢复动态平衡的机制。从整体上看， 系统方法，我们调查了单个(流感或葡萄球菌)期间的炎症反应 金黄色葡萄球菌)和双重感染(流感/金黄色葡萄球菌)。我们进行了转录和脂肪组学分析 样本来自一种小鼠的超级感染模型。我们的脂肪组学分析集中在二十烷类化合物上，因为它们 在诱导和消退炎症方面发挥关键作用。与单一感染相比，我们发现 在超级感染期间，过量生产一组二十烷类化合物。这些脂类(抗炎细胞色素P450脂类 介质，主要是DHET)可以激活核受体和转录因子PPARa和PPARg。 在流感单一感染期间，在解决期适度诱导CYP脂类(主要是EET) 允许适当的抗炎反应，以促进体内平衡的恢复。我们假设 虽然EET促进微生物感染后炎症的生理消退，但DHET在 重叠感染时的异常水平导致巨噬细胞极化的改变和抑制 细菌清除。未能控制细菌病原体放大了免疫信号以招募额外的 最终导致不可逆转的组织损伤的免疫细胞。期间，我们将采取以下方法 研究二十烷醇-PPAR轴对炎症反应的影响。 首先，我们将确定扰动二十烷-PPAR轴对分辨率或放大的影响 单重感染时的炎症反应。我们将结合使用化学抑制剂和基因 建立模型，以确定动物在单次和超短期内是否会受到保护或死于疾病 感染。我们将确定脂肪组谱，以评估抑制剂对血管内皮细胞的特异性影响。 二十烷类新陈代谢网络。我们还将测定细菌/病毒载量、细胞密度、病理组织学和 巨噬细胞的靶向转录图谱。第二，我们将确定通过什么机制 二十烷基烷类化合物激活的PPARα/γ调节免疫信号、巨噬细胞极化和免疫代谢 在试管中。巨噬细胞极化(经典激活或交替激活)可放大或消解炎症 回应。我们将确定不同的细胞色素P450代谢产物在小鼠体内激活PPARα/γ的效力 和原代人类巨噬细胞。我们将确定二十烷类化合物(细胞色素P450代谢物)如何影响免疫。 信号、巨噬细胞极化和脂类代谢。有趣的是，虽然炎症的诱导 一直是积极研究的对象，消退炎症的机制一直是 难以捉摸。通过深入了解单一感染和双重感染期间炎症的消退，我们将开发出 感染和免疫相关人类疾病的新治疗靶点。