Macrophage transcriptional responses to Legionella pneumophila

描述（由申请方提供）：嗜肺军团菌是一种新出现的传染病威胁的典型例子。最近来自几个实验室的令人兴奋的数据表明，I型干扰素（IFN）是许多（如果不是全部）细胞内病原体感染的重要标志。我们的假设是，胞质监视途径检测军团菌衍生的配体在胞质中导致I型干扰素和共调节基因的转录诱导。初步数据表明，I型干扰素是由军团菌以依赖于L。嗜肺菌的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。刺激宿主产生干扰素的假定军团菌衍生配体是未知的，但我们的初步研究已经确定Mda 5作为军团菌的关键宿主传感器。嗜肺菌由于Mda 5是RNA的胞质传感器，我们的发现表明令人兴奋的可能性，L。嗜肺菌可以将细菌RNA易位到宿主细胞胞质溶胶中。即使L.尽管Mda 5感测嗜肺菌，但我们的结果挑战了现有的范例，因为Mda 5被广泛认为仅仅是病毒而不是细菌的传感器。因此，我们的具体目标是：1。鉴定和表征L的分子决定簇。嗜肺菌，其正或负调节宿主I型干扰素的产生。2.表征感受L的宿主途径。嗜肺菌在胞质溶胶中，导致I型干扰素和其他基因的转录诱导。3.确定胞质感应和I型干扰素在抗乳酸杆菌天然免疫中的作用。pneumophila使用体外和体内模型。公共卫生相关性：嗜肺军团菌是一种在巨噬细胞宿主细胞中复制的细菌，从而引起一种严重的，通常是致命的，称为军团菌病的肺炎。在这项提案中，我们试图使用军团菌作为模型来了解巨噬细胞如何感知和防御感染，最终目标是利用这些信息开发更有效的治疗方法和疫苗。

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.