Macrophage transcriptional responses to Legionella pneumophila

巨噬细胞对嗜肺军团菌的转录反应

• 批准号: 8260351
• 负责人: RUSSELL E VANCE
• 金额: $ 32.39万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260351
• 关键词: Accounting; Bacteria; Bacterial RNA; Cells; Cytosol; Data; Emerging Communicable Diseases; Genes; Goals; Health; Host Defense; Immune; Immune response; Immune system; In Vitro; Infection; Interferon Type I; Interferons; Knockout Mice; Legionella; Legionella pneumophila; Legionnaires' Disease; Libraries; Ligands; Modeling; Molecular; Molecular Profiling; Natural Immunity; Nature; Pathway interactions; Pneumonia; Production; Proteins; RNA; Role; Screening procedure; Signal Pathway; System; Testing; Virus; in vivo Model; insight; macrophage; microorganism; mutant; novel; pathogen; response; sensor; therapeutic vaccine; tool

DESCRIPTION (provided by applicant): Legionella pneumophila is a protypical example of an emerging infectious disease threat. Recent exciting data from several labs have indicated that type I interferons (IFNs) are an important signature of infection with many, if not all, intracellular pathogens. Our hypothesis is that a cytosolic surveillance pathway detects Legionella-derived ligands in the cytosol leading to the transcriptional induction of type I IFNs and coregulated genes. Preliminary data indicate that type I interferons are induced by Legionella in a manner dependent on L. pneumophila's type IV (Dot/Icm) secretion system. We also find that type I interferons are required to restrict intracellular replication of Legionella. The putative Legionella-derived ligand that stimulates host production of interferon is unknown, but our preliminary studies have identified Mda5 as a key host sensor of L. pneumophila. Since Mda5 is a cytosolic sensor of RNA, our finding suggests the exciting possibility that L. pneumophila may translocate bacterial RNA into the host cell cytosol. Even if a non-RNA ligand from L. pneumophila is sensed by Mda5, our results challenge existing paradigms since Mda5 is widely believed to be solely a sensor of viruses, rather than of bacteria. Thus, our specific aims are: 1. Identify and characterize molecular determinants of L. pneumophila that positively or negatively regulate host production of type I interferon. 2. Characterize the host pathways that sense L. pneumophila in the cytosol, leading to transcriptional induction of type I interferon and other genes. 3. Determine the role of cytosolic sensing and type I interferons in innate immunity against L. pneumophila using in vitro and in vivo models. PUBLIC HEALTH RELEVANCE: Legionella pneumophila is a bacterium that replicates in host cells called macrophages, thereby causing a severe, and often lethal, pneumonia called Legionnaires' Disease. In this proposal we seek to use Legionella as a model for understanding how macrophages sense and defend against infection, with the ultimate goal of using this information to develop more effective therapeutics and vaccines.

描述（由申请人提供）：肺炎军团菌是新兴的传染病威胁的原型例子。来自几个实验室的最新令人兴奋的数据表明，I型干扰素（IFN）是与许多（如果不是全部）细胞内病原体感染的重要特征。我们的假设是，胞质监测途径检测到胞质溶胶中的军团菌衍生的配体，导致I型IFN和核心测定基因的转录诱导。初步数据表明，I型干扰素是由Legionella诱导的，其方式取决于肺炎乳杆菌IV型（DOT/ICM）分泌系统。我们还发现，I型干扰素需要限制军团菌的细胞内复制。刺激干扰素宿主产生的假定军团衍生的配体尚不清楚，但是我们的初步研究已将MDA5鉴定为肺炎乳杆菌的关键宿主传感器。由于MDA5是RNA的胞质传感器，因此我们的发现表明，肺炎乳杆菌可能会将细菌RNA转移到宿主细胞胞质溶胶中的令人兴奋的可能性。即使MDA5感受到肺炎乳杆菌的非RNA配体，我们的结果挑战了现有的范式，因为MDA5被广泛认为仅是病毒的传感器，而不是细菌。因此，我们的具体目的是：1。识别和表征肺炎乳杆菌的分子决定因素，它们积极或负调节I型干扰素的宿主产生。 2。表征宿主途径，即在细胞质中遇到肺炎乳杆菌，从而导致I型干扰素和其他基因的转录诱导。 3。使用体外和体内模型来确定胞质感应和I型干扰素在对肺炎乳杆菌的先天免疫中的作用。公共卫生相关性：肺炎军团菌是一种在称为巨噬细胞的宿主细胞中复制的细菌，从而导致严重且经常致命的肺炎，称为军团纳尔氏病。在此提案中，我们试图使用军团菌作为了解巨噬细胞如何感知和防御感染的模型，其最终目标是使用这些信息来开发更有效的治疗剂和疫苗。