Characterization of Legionella virulence mechanisms

军团菌毒力机制的表征

• 批准号: 8553977
• 负责人: Matthias Machner
• 金额: $ 84.79万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8553977
• 关键词: Air Conditioning; Alveolar Macrophages; Amoeba genus; Bacteria; Bacterial Proteins; Biological; Breathing; Cells; Cytosol; Deposition; Development; Disease; Endoplasmic Reticulum; Environment; Event; Foundations; Fresh Water; Funding; Goals; Golgi Apparatus; Guanine; Guanosine Triphosphate; Habitats; Human; Hydrolysis; Immune; Individual; Legionella; Legionella pneumophila; Legionnaires' Disease; Lung; Molecular; Organism; Parasites; Pneumonia; Post-Translational Protein Processing; Process; Proteins; Research Project Grants; Respiratory Tract Infections; Role; Route; Sequence Homology; Signal Transduction; System; Therapeutic; Transmembrane Transport; Transport Vesicles; Vacuole; Virulence; Water; insight; macrophage; man; microorganism; novel; pathogen; research study

We investigate how the bacterium Legionella pneumophila can exploit human cells and cause a severe pneumonia known as Legionnaires disease. L. pneumophila is commonly found in habitats containing freshwater where it thrives as a natural parasite of unicellular organisms such as amoeba. When inhaled by humans, L. pneumophila can infect alveolar macrophages and cause a respiratory infection that is fatal for up to 30 percent of infected individuals. The ability of this opportunistic pathogen to establish a replication vacuole within infected cells is key to its virulence. The bacterium delivers several proteins, so called effectors, into the host cytosol where they alter host signaling events in order to create an environment supportive for the bacteriums replication cycle. Over the past funding period we have shown that some of the effector proteins alter host membrane transport between the endoplasmic reticulum and the Golgi compartment. The precise mechanism of how transport vesicles are hijacked by L. pneumophila is just beginning to unfold and remains the main focus of this research study. In particular, we analyze L. pneumophila effector proteins that manipulate the activity of the small guanine triphosphatase (GTPase) Rab1, one of the key regulators of this vesicle transport route. Some of these L. pneumophila effectors appear to be molecular mimics of human proteins that catalyze Rab1 activation through GDP/GTP exchange and Rab1 deactivation through hydrolysis of GTP. In addition, we discovered a second regulator circuit unique to L. pneumophila in which bacterial effector proteins attach or remove a post-translational modification to Rab1 in order to stabilize its activation state. This novel concept has not been described in any other virulence system and is the focus of our ongoing studies. The results obtained here will provide important insight into the virulence strategies of L. pneumophila and create the foundation for the development of better therapeutic approaches to treat Legionnaires disease and related illnesses.

我们调查嗜肺军团菌如何利用人类细胞并引起严重的肺炎，即军团病。嗜肺乳杆菌通常存在于含有淡水的栖息地，在那里它作为单细胞生物（如变形虫）的天然寄生虫茁壮成长。当被人类吸入时，嗜肺乳杆菌可以感染肺泡巨噬细胞并引起呼吸道感染，对高达30%的感染者来说是致命的。这种机会性病原体在受感染细胞内建立复制液泡的能力是其毒性的关键。细菌将几种被称为效应物的蛋白质传递到宿主细胞质中，在那里它们改变宿主的信号事件，以创造一个支持细菌复制周期的环境。在过去的资助期间，我们已经表明，一些效应蛋白改变宿主膜运输之间的内质网和高尔基室。嗜肺乳杆菌劫持转运囊泡的确切机制才刚刚开始揭示，这仍然是本研究的主要焦点。特别是，我们分析了操纵小鸟嘌呤三磷酸酶（GTPase） Rab1活性的嗜肺乳杆菌效应蛋白，该蛋白是该囊泡运输途径的关键调节因子之一。其中一些嗜肺乳杆菌效应物似乎是人类蛋白质的分子模拟物，通过GDP/GTP交换催化Rab1活化，通过GTP水解催化Rab1失活。此外，我们还发现了嗜肺乳杆菌特有的第二种调节回路，其中细菌效应蛋白附着或去除Rab1的翻译后修饰，以稳定其激活状态。这一新颖的概念尚未在任何其他毒力系统中描述，是我们正在进行的研究的重点。本文获得的结果将为嗜肺乳杆菌的毒力策略提供重要的见解，并为开发更好的治疗方法来治疗军团病和相关疾病奠定基础。