Lung Macrophage Memory Development and Responses in Secondary Pneumonia and Sepsis

继发性肺炎和脓毒症中肺巨噬细胞记忆的发育和反应

• 批准号: 10317455
• 负责人: Bibhuti Bhusan Mishra
• 金额: $ 61.09万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-27 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10317455
• 关键词: Address; Airway Disease; Alveolar Macrophages; Atherosclerosis; Bacteria; Bacterial Infections; Bacterial Pneumonia; Cells; Characteristics; Chromatin Remodeling Factor; Cicatrix; Clinical; Complication; DNA Polymerase II; DNA-Directed RNA Polymerase; Data; Defect; Dendritic Cells; Development; Disease; Environment; Epigenetic Process; Exhibits; Experimental Models; Fostering; Functional disorder; Future; Gatekeeping; Gene Expression; Genes; Genetic Transcription; Goals; Gram-Positive Bacteria; Immune; Immune Tolerance; Immune response; Immunity; Immunologic Factors; Immunologic Memory; Immunologics; Immunology; Immunosuppression; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza; Interferon Type II; Interferons; Invaded; Klebsiella pneumoniae; Knowledge; Limes; Lung; Lung Inflammation; Malignant Neoplasms; Measures; Mediating; Memory; Molecular; Mus; Nature; Outcome; Pathologic; Pathology; Patients; Phagocytes; Phase; Phenotype; Play; Pneumococcal Pneumonia; Pneumonia; Predisposition; Primary Infection; Process; Protein Inhibition; Protein-Arginine N-Methyltransferase; Proteins; Recovery; Reporting; Resolution; Role; Secondary to; Sepsis; Severity of illness; Staphylococcus aureus; Stimulus; Streptococcus pneumoniae; T-Lymphocyte; Techniques; Therapeutic; Time; Training; Transcription Initiation Site; Transcriptional Activation; Transforming Growth Factor beta; Vaccination; Virus Diseases; Work; base; clinically relevant; combat; cytokine; cytokine release syndrome; design; genome-wide; imprint; influenza infection; insight; macrophage; new therapeutic target; novel; pathogen; pathogenic bacteria; prevent; promoter; recruit; response; secondary infection; transcriptional reprogramming; tumor-immune system interactions

Project Summary Increased susceptibility to secondary bacterial pneumonia is a significant clinical complication of pulmonary viral infections. The characterization of molecular players that leave immunological scars/memory for sustained periods after clinical recovery from viral infections is vital for preventing secondary pneumonic infections. Our current knowledge in this regard is vastly limited, and the studies so far have mainly focused on “immunologically tolerized” dendritic cells and macrophages developing as a result of immunosuppressive microenvironment established upon resolution of primary infection. In this application, based on our strong supportive data (communicated to Nature Immunology) showing that IFNγ produced during pulmonary influenza infection imprints an immunological memory in alveolar macrophages (AMs) that drive a pathologic innate memory response to a subsequent bacterial pathogen, we propose to identify the novel mechanism of transcriptional reprogramming in these immunologically trained AMs. In this regard, pausing of RNA polymerase II (Pol II) at the transcriptional start site of most mammalian genes and its release onto the gene body for rapid transcription upon cellular activation is a key step in determination of transcriptional activation. By using state-of-the art genome-wide techniques, we have found that IFNγ responsive genes in macrophages acquire Pol II enrichment at the promotor-proximal regions during their transcriptional induction phase that controls simultaneous elongation and subsequent gene expression. We termed this novel mechanism Acquired Promoter-proximal Pol II enrichment (APPe), and propose that APPe is responsible for IFN-induced memory phenotype in influenza infection. Further, we found that chromatin modifier Protein Arginine Methyltransferase 8 (PRMT8) is involved in IFN-induced memory response by establishing APPe early in trained-macrophages. Based on these data, we will determine: (Aim 1) how PRMT8 controls IFN-induced memory transcriptional reprogramming responsible for an earlier and greater transcription of IFN-responsive genes in these trained AMs upon reactivation during secondary bacterial infection, and whether PRMT8 deficiency ameliorates pathology and reinstates an appropriate immune response to secondary bacterial infection by both Gram-negative (Klebsiella pneumoniae) and Gram-positive bacteria (Staphylococcus aureus, and Streptococcus pneumoniae/ pneumococcus); (Aim 2) how transcriptional memory outcomes in AMs during secondary bacterial pneumonia are regulated through the rate-liming step of APPe via PRMT8 mediated APPe occurrence for an early, uncontrolled transcription of target genes that are involved in cytokine storm and later severe sepsis. The successful completion of proposed work will address a major gap in our knowledge of mechanisms dictating macrophage functions during influenza and subsequent bacterial infections, which will have implications for future therapeutic measures.

项目摘要 继发性细菌性肺炎的易感性增加是肺部病毒的重要临床并发症 感染。留下免疫疤痕/记忆的分子玩家的特征 从病毒感染临床康复后的一段时间对于预防继发性肺炎感染至关重要。我们的 目前在这方面的知识非常有限，到目前为止，研究主要集中在“免疫学”上 免疫抑制微环境导致的“耐受”树突状细胞和巨噬细胞 建立在解决原发感染的基础上。在此应用程序中，基于我们强大的支持性数据 (传达给自然免疫学)显示干扰素γ在肺部流感感染期间产生 在肺泡巨噬细胞(AM)中印记免疫记忆，从而驱动病理性的先天记忆 对随后的细菌病原体的反应，我们建议确定转录的新机制 在这些经过免疫训练的AM中重新编程。在这方面，暂停RNA聚合酶II(POL II)在 大多数哺乳动物基因的转录起始点及其释放到基因体上以进行快速转录 在细胞激活时是决定转录激活的关键步骤。通过使用最先进的 全基因组技术，我们发现巨噬细胞中干扰素γ反应基因获得POL II浓缩 在转录诱导阶段的启动子-近端区域同时控制 伸长和随后的基因表达。我们将这种新的机制称为获得性启动子-近端极 II富集(APPE)，并认为APPE与流感病毒干扰素诱导的记忆表型有关 感染。此外，我们还发现染色质修饰蛋白精氨酸甲基转移酶8(PRMT8)参与了 干扰素通过在训练性巨噬细胞早期建立APE诱导记忆反应。根据这些数据，我们 将决定：(目标1)PRMT8如何控制干扰素诱导的记忆转录重编程负责 在这些训练有素的AM中，当重新激活时，干扰素反应基因的早期和更大的转录 继发性细菌感染，以及PRMT8缺乏是否改善病理并恢复 对革兰氏阴性杆菌(肺炎克雷伯菌)继发细菌感染的适当免疫反应 和革兰氏阳性菌(金黄色葡萄球菌和肺炎链球菌/肺炎球菌)；(目标2) 继发性细菌性肺炎期间AM的转录记忆结果是如何通过 通过PRMT8介导的APPE发生的速率限制步骤，用于靶标的早期、不受控制的转录 参与细胞因子风暴和后来的严重脓毒症的基因。拟议工作的圆满完成 将解决我们在流感和流感期间决定巨噬细胞功能的机制方面的一个主要空白 随后的细菌感染，这将对未来的治疗措施产生影响。