Anti-inflammatory bioactive lipids exacerbating Staphylococcus aureus infection post influenza

抗炎生物活性脂质加剧流感后金黄色葡萄球菌感染

• 批准号: 9979757
• 负责人: Vincent Tam
• 金额: $ 19.81万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-17 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979757
• 关键词: Affect; Agonist; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antibiotic Resistance; Automobile Driving; Bacteria; Bacterial Infections; Binding; Cells; Cessation of life; Chemicals; Child; Clinical; Complex; Complication; Disease; Eicosanoids; Elderly; Ensure; Enzymes; Exposure to; Genes; Genetic; Genetic Transcription; Goals; Homeostasis; Human; Immune; Immune response; Immune signaling; Immune system; Immunologics; Immunotherapeutic agent; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Influenza; Innate Immune Response; Investigation; Ligands; Lipids; Mass Spectrum Analysis; Mediating; Metabolic Pathway; Modeling; Molecular; Morbidity - disease rate; Mus; Neutrophilic Infiltrate; Nuclear Receptors; Organism; Pathologic; Patients; Phase; Phenotype; Physiological; Play; Pneumonia; Population; Production; Regulation; Research; Resolution; Role; Sampling; Signal Transduction; Signaling Molecule; Sorting - Cell Movement; Staphylococcus aureus; Staphylococcus aureus infection; Systems Biology; Time; Tissues; Transcript; Transcriptional Regulation; Tumor-infiltrating immune cells; Vaccines; Vancomycin-resistant S. aureus; cell type; clinically relevant; human disease; improved; influenzavirus; inhibitor/antagonist; innate immune function; insight; lipid mediator; methicillin resistant Staphylococcus aureus; microbial; monocyte; mortality; mouse model; nano-string; neutrophil; novel; novel therapeutics; pandemic influenza; pathogen; pathogenic bacteria; pathogenic microbe; protein protein interaction; recruit; resistant strain; response; small hairpin RNA; superinfection; therapeutic target; transcription factor

PROJECT SUMMARY/ABSTRACT Secondary bacterial infection following influenza (super-infection) is a serious clinical complication that often leads to pneumonia and death in patients. In most infection models, a single species or organism of microbial pathogen is used to induce an insult or disease in the host. However, humans are constantly exposed to a multitude of microbial pathogens simultaneously. The resulting signaling crosstalk in the immune system has largely been overlooked. An unbiased, holistic systems biology approach, therefore, is required to decipher the molecular interactions between the mammalian host, influenza virus and the bacterial pathogen. We have previously used this approach to study the immune response during 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. We focused our lipidomic analysis on eicosanoids because they are signaling molecules that play critical roles in the induction and resolution of inflammation. During super- infection, when compared to single infections, anti-inflammatory CYP450 metabolites, natural ligands for the nuclear receptor PPARa, were produced at a significantly higher level. We hypothesize that these lipids normally promote the physiological resolution of inflammation. However, during super-infection, CYP450 metabolites are produced at a pathological level leading to an over-activation of PPARa in innate immune cells. The activation of PPARa, in turn, compromises the anti-bacterial function of neutrophils and monocytes. The persistence of bacteria provides immune signals that amplify a feedforward loop to recruit more immune cells, thus contributing to tissue damage and eventual mortality. We will take the following approaches during single and super-infection to investigate the effects of the bioactive lipids-PPARa axis on the innate immune function and signaling. First, we will identify the transcriptional networks of infiltrating neutrophils and monocytes, the predominant cell types recruited to clear bacterial pathogens during S. aureus infection with or without prior influenza. We will further characterize the anti-bacterial function of the neutrophils and monocytes in the presence of genetic (wildtype C57/Bl6 versus Ppara–/– mice) and chemical (agonists and inhibitors against PPARa) perturbations. Using shRNA and gene editing, we will determine the genetic interactors of PPARa which collaborate to alter the transcriptional response. Second, we will determine the lipidomic landscape during the late phase of super-infection when bacterial persistence triggers further infiltration of immune cells. We will investigate whether using chemical inhibitors against PPARa and the eicosanoid metabolic pathways can alleviate the increased morbidity and mortality phenotype during super-infection. Using transcriptional and lipidomic approaches to study the bioactive lipids-PPARa axis during single and super-infection will provide significant insights into the mechanisms driving immune cross-talk during super- infections and identify novel host-directed therapeutic targets for influenza.

项目摘要/摘要 流感后的继发性细菌感染(重叠感染)是一种严重的临床并发症，通常 会导致肺炎和病人死亡。在大多数感染模型中，单一的微生物物种或有机体 病原体是用来在宿主体内引起侮辱或疾病的。然而，人类经常接触到一种 多种微生物病原体同时存在。由此产生的免疫系统中的信号串扰 在很大程度上被忽视了。因此，需要一种公正的、整体的系统生物学方法来破译 哺乳动物宿主、流感病毒和细菌病原体之间的分子相互作用。我们有 以前使用这种方法来研究单一(流感或葡萄球菌)期间的免疫反应 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 是在炎症的诱导和消退中发挥关键作用的信号分子。在超级- 感染，当与单一感染相比，抗炎细胞色素P450代谢物，天然配体用于 核受体PPARa的产生水平显著高于对照组。我们假设这些脂类 正常情况下促进生理消退炎症。然而，在超级感染期间，细胞色素P450 代谢产物是在病理水平上产生的，导致先天免疫中PPARa的过度激活 细胞。PPARa的激活反过来会损害中性粒细胞和单核细胞的抗菌功能。 细菌的持久性提供了免疫信号，放大了前馈环路以招募更多的免疫 细胞，从而导致组织损伤和最终死亡。期间，我们将采取以下方法 研究生物活性脂类PPARa轴对天然免疫功能的影响 功能和信令。首先，我们将确定浸润性中性粒细胞和 单核细胞，在金黄色葡萄球菌感染或感染期间被招募来清除细菌病原体的主要细胞类型 没有患过流感。我们将进一步研究中性粒细胞和单核细胞的抗菌功能。 在存在遗传(野生型C57/BL6与Ppara-/-小鼠)和化学(激动剂和抑制剂)的情况下 对抗PPARA)扰动。利用shRNA和基因编辑，我们将确定 PPARa协同改变转录反应。第二，我们将测定脂肪组体 超级感染后期的景观，此时细菌的持久性引发了进一步的渗透 免疫细胞。我们将调查是否使用化学抑制剂来对抗PPARa和二十烷类化合物 代谢途径可以缓解重叠感染时增加的发病率和死亡率。 用转录和脂组学方法研究单细胞和多细胞周期中生物活性脂质-PPARa轴 超级感染将为在超级感染过程中驱动免疫串扰的机制提供重要的见解 感染和确定新的宿主导向的流感治疗靶点。