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

基本信息

批准号：
10661028
负责人：
Bibhuti Bhusan Mishra
金额：
$ 65.29万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
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/10661028
关键词：
Acceleration Airway Disease Alveolar Macrophages Atherosclerosis Bacteria Bacterial Infections Bacterial Pneumonia Cells Characteristics Chromatin Remodeling Factor Cicatrix Clinical Communication Complication 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 Inflammatory Inflammatory Response Influenza Interferon Type II Interferons Invaded Klebsiella pneumoniae Knowledge Limes Lung Macrophage Malignant Neoplasms Measures Mediating Memory Molecular Mus Nature Outcome Pathologic Pathology Patients Phagocytes Phase Phenotype Play Pneumonia Polymerase Predisposition Primary Infection Process Productivity Protein Inhibition Protein-Arginine N-Methyltransferase Proteins Pulmonary Inflammation RNA Polymerase II 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 clinically relevant combat cytokine cytokine release syndrome design genome-wide imprint influenza infection insight new therapeutic target novel pathogen pathogenic bacteria prevent promoter recruit response secondary infection transcriptional reprogramming tumor-immune system interactions

项目摘要

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.

项目摘要对继发细菌性肺炎的敏感性增加是肺病毒的显着临床并发症感染。留下免疫疤痕/记忆的分子玩家的表征从病毒感染中恢复临床后的周期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” 免疫抑制微环境的耐受性”树突状细胞和巨噬细胞发展建立在原发性感染的分辨率之后。在此应用程序中，基于我们强大的支持数据（传达与自然免疫学的传播）表明在肺部影响力感染过程中产生的IFNγ 在肺泡巨噬细胞（AMS）中烙印的烙印，该记忆驱动病理性记忆对随后的细菌病原体的反应，我们建议识别转录的新机制在这些经过免疫学训练的AM中重新编程。在这方面，RNA聚合酶II（POL II）的暂停大多数哺乳动物基因的转录起始位点及其释放到基因体中以进行快速转录细胞激活是确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的IFNγ响应基因获取POL II酶在其转录感应阶段，在启动子促进区域，同时控制伸长和随后的基因表达。我们称这种新型机制获得了启动子pol II富集（APPE），并提出APPE负责IFN诱导的记忆表型感染。此外，我们发现染色质修饰蛋白蛋白精氨酸甲基转移酶8（PRMT8）参与通过在训练有素的巨噬细胞中建立APPE，IFN引起的记忆响应。基于这些数据，我们将确定：（ AIM 1）PRMT8如何控制IFN诱导的内存转录重新编程负责在这些训练的AM中重新激活的IFN响应基因的早期和更大的转录次生细菌感染以及PRMT8缺乏能够改善病理并恢复通过革兰氏阴性菌（肺炎克雷伯氏菌）对继发细菌感染的适当免疫响应和革兰氏阳性细菌（金黄色葡萄球菌和肺炎链球菌/肺炎球菌）；（目标2）在次生细菌肺炎期间AMS中的转录记忆结果如何通过通过PRMT8介导的APPE发生的APPE的速率限制步骤，用于早期，不受控制的目标转录涉及细胞因子风暴和后来严重败血症的基因。拟议工作的成功完成将解决我们对影响力巨噬细胞功能的机制知识的主要差距随后的细菌感染将对未来的治疗措施产生影响。