Novel approaches to identify host genes required for Chlamydia pathogenesis

性状（由申请方提供）：沙眼衣原体和衣原体。肺炎是人类感染和疾病的重要原因。C.沙眼是第三世界非先天性失明的主要原因，也是西方国家性传播疾病和非先天性不育的主要原因。C.肺炎引起广泛的呼吸道感染。这些疾病的异常流行和种类，以及它们导致不育、失明和各种慢性状态的能力，使它们成为公众关注的问题。 第一重要性。虽然感染可以用抗生素治疗，但没有一种药物具有足够的成本效益，足以在不发达国家广泛消除这种疾病，疫苗的尝试也没有成功。由于缺乏衣原体遗传学，对生命周期和发病机制的详细了解受到阻碍，但我们现在通过监测其对宿主细胞生物学的影响，在了解衣原体发病机制方面取得了重大进展。这些研究对于确定新的战略至关重要 来治疗和预防。 所有衣原体属都是专性细胞内寄生虫，它们必须建立一个特殊的小生境（称为内含物的膜结合区室），以便在不利的细胞内环境中生存和复制。我们实验室和其他人最近的变革性研究表明，内含物不是一个孤立的隔间，没有与宿主的相互作用。相反，我们现在了解到，衣原体，尽管其基因组大小小，编码远远超过100个蛋白质分泌的功能，选择性地招募细胞器和操纵宿主细胞运输途径，使衣原体获得必需的营养物质和逃避检测宿主免疫反应。事实上，宿主细胞运输途径的颠覆正在成为成功的细胞内微生物的共同主题。进一步解开这些复杂的事件将产生重要的线索，传染病的发病机制，以及提供新的见解基本真核细胞生物学，从发育生物学的影响，癌症生物学。我们的短期目标如下：目标1。我们将研究C。沙眼衣原体利用Arf 1建立独特的细胞内生态位。目标2.我们将调查的假设，衣原体建立了一个“现场”的脂质生物合成工厂在包涵体膜是必要的细菌复制和包涵体的生长和稳定性。目标3.我们将使用 本领域的生物化学和成像技术，以获得衣原体包涵体融合的机理理解。总之，这些发现将增加我们对细胞内感染发病机制的基本知识。此外，它们有可能为开发新的治疗、诊断和预防疗法确定新的靶点。

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.