Novel approaches to identify host genes required for Chlamydia pathogenesis

鉴定衣原体发病机制所需宿主基因的新方法

• 批准号: 8549939
• 负责人: Joanne N. Engel
• 金额: $ 36.93万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8549939
• 关键词: Affect; Antibiotics; Binding; Biochemical; Biogenesis; Biological; Blindness; Cancer Biology; Cells; Cellular biology; Ceramides; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Chlamydophila pneumoniae; Chronic; Chronic Disease; Communicable Diseases; Complex; Country; Detection; Developing Countries; Development; Developmental Biology; Diagnostic; Disease; Drosophila genus; Environment; Enzymes; Eukaryotic Cell; Event; Genes; Genetic; Genome; Goals; Golgi Apparatus; Grant; Growth; Guanosine Triphosphate Phosphohydrolases; Human; Human Characteristics; Imaging Techniques; Immune response; Infection; Infertility; Knowledge; Lead; Learning; Life Cycle Stages; Lipids; Membrane; Microbe; Microscopy; Monitor; Monomeric GTP-Binding Proteins; Nutrient; Organelles; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Play; Prevalence; Prevention; Process; Protein-Serine-Threonine Kinases; Proteins; RNA Interference; Recruitment Activity; Research; Resolution; Respiratory Tract Infections; Role; Route; Sexually Transmitted Diseases; Site; Sphingolipids; Sphingomyelins; Sterols; Technology; Testing; Time; Vaccines; Variant; base; cost; cost effective; genome-wide; high risk; human disease; innovation; insight; novel; novel strategies; novel therapeutics; obligate intracellular parasite; protein function; protein kinase D; research study; sphingomyelin synthase; success; tissue/cell culture; trafficking; treatment strategy

DESCRIPTION (provided by applicant): Chlamydia trachomatis and C. pneumoniae are important causes of human infections and disease. C. trachomatis , is the major cause of non-congenital blindness in the third world and a leading cause of sexually transmitted diseases and non-congenital infertility in Western countries. C. pneumoniae causes a wide range of respiratory infections. The extraordinary prevalence and array of these diseases as well as their capacity to lead to infertility, blindness, and various chronic states make them public concerns of the first importance. Although infections can be treated with antibiotics, no drug is cost-effectiv enough for widespread elimination of the disease in underdeveloped countries, and attempts at vaccines have been unsuccessful. A detailed understanding of the life cycle and the mechanisms of pathogenesis have been hindered by the lack of Chlamydia genetics, but we have now made substantial inroads into understanding Chlamydia pathogenesis by monitoring its effects on the cell biology of the host. These studies are essential to identify new strategies for treatment and prevention. All Chlamydia species are obligate intracellular parasites that must establish a privileged niche (a membrane bound compartment termed the inclusion) in order to survive and replicate in the hostile intracellular environment. Recent transformative research from our lab and others reveals that the inclusion is not an isolated compartment devoid of interactions with the host. Instead, we now understand that Chlamydia, despite its small genome size, encodes well over 100 proteins that are secreted that function to selectively recruit organelles and to manipulate host cell trafficking pathways, allowing Chlamydia to acquire essential nutrients and escape detection by the host immune response. Indeed, subversion of host cell trafficking pathways is emerging as a common theme in successful intracellular microbes. Further unraveling these complex events will yield important clues into the pathogenesis of infectious disease as well as provide novel insights into fundamental eukaryotic cell biology, with implications ranging from developmental biology to cancer biology. Our short term goals are as follows: Aim 1. We will investigate how C. trachomatis utilizes Arf1 to establish a unique intracellular niche. Aim 2. We will investigate the hypothesis that Chlamydia establishes an "onsite" lipid biosynthetic factory at the inclusion membrane that is necessary for bacterial replication and inclusion growth and stability. Aim 3. We will use state of the art biochemical and imaging techniques to gain a mechanistic understand of chlamydial inclusion fusion. Together, these findings will increase our basic knowledge of the pathogenesis of intracellular infections. In addition, they have the potential to identify new targets for the development of new therapeutic, diagnostic, and preventative therapies.

描述（由申请人提供）：沙眼衣原体和肺炎梭菌是人类感染和疾病的重要原因。沙眼梭状芽胞盘是第三世界非征否失明的主要原因，也是西方国家的性传播疾病和非中国不孕症的主要原因。 C.肺炎会引起广泛的呼吸道感染。这些疾病的特殊患病率和阵列以及它们导致不育，失明和各种慢性国家的能力使他们成为公众的关注 第一个重要性。尽管可以用抗生素治疗感染，但没有足够的成本效应，可以广泛地消除欠发达国家的疾病，并且尝试使用疫苗的尝试未能成功。缺乏衣原体遗传学对生命周期和发病机理的详细理解受到了阻碍，但是我们现在通过监测其对宿主细胞生物学的影响来了解衣原体发病机理的大量了解。这些研究对于确定新策略至关重要 用于治疗和预防。 所有衣原体物种都是义务的细胞内寄生虫，必须建立一个特权的生态位（一种称为包容性的膜结合的隔室），以便在敌对的细胞内环境中生存和复制。我们实验室和其他实验室的最新变革性研究表明，包含不是与宿主相互作用的孤立隔室。取而代之的是，我们现在知道，衣原体尽管具有较小的基因组大小，但仍编码超过100种蛋白质，这些蛋白质被分泌为有选择性地募集细胞器并操纵宿主细胞运输途径，从而使衣原体可以获取必要的营养素并通过宿主免疫反应获得必需的营养素。实际上，颠覆宿主细胞运输途径正在成为成功细胞内微生物中的共同主题。进一步阐明这些复杂事件将为传染病的发病机理带来重要的线索，并提供对基本真核生物细胞生物学的新见解，其影响从发育生物学到癌症生物学。我们的短期目标如下：AIM 1。我们将研究沙眼梭状芽孢杆菌如何利用ARF1建立独特的细胞内生态位。目标2。我们将研究衣原体在包含膜上建立“现场”脂质生物合成工厂的假设，这是细菌复制，包容性生长和稳定性所必需的。目标3。我们将使用状态 艺术生化和成像技术，以了解对衣原体包容融合的机械性。总之，这些发现将增加我们对细胞内感染发病机理的基本知识。此外，他们有可能确定新的治疗，诊断和预防疗法的新目标。