Role of the Coxiella burnetii Cryptic Plasmid in Host Cell Parasitism

伯氏柯克斯体隐匿质粒在宿主细胞寄生中的作用

• 批准号: 8676637
• 负责人: Daniel E Voth
• 金额: $ 40.79万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676637
• 关键词: Acute; Acute Disease; Address; Aerosols; Alveolar; Apoptosis; Area; Autophagosome; Bacterial Proteins; Binding; Biology; Cavia; Cell Culture Techniques; Cell Survival; Cell physiology; Cells; Cellular biology; Chromosomes; Chromosomes, Human, Pair 8; Chronic; Coxiella; Coxiella burnetii; Cytoplasm; Cytosol; DNA; Endocarditis; Event; F Box Domain; Genes; Goals; Golgi Apparatus; Human; Immune Sera; In Vitro; Individual; Infection; Kinesin; Lysosomes; Mammalian Cell; Mediating; Membrane; Methods; Modeling; Mononuclear; Mutation; Organelles; Organism; Outcome; Pathogenesis; Phagocytes; Plasmids; Play; Process; Production; Protein Binding; Protein Biosynthesis; Proteins; Q Fever; Research; Role; System; Therapeutic; Type IV Secretion System Pathway; Vacuole; Virulence; Virulence Factors; Zoonoses; combat; design; flu; in vivo; insight; novel; obligate intracellular parasite; parasitism; pathogen; public health relevance; research study; therapeutic target; trafficking

DESCRIPTION (provided by applicant): Coxiella burnetii is an intracellular bacterial pathogen and the etiologic agent of human Q fever, an acute debilitating flu-like illness that can progress to chronic endocarditis. Since its discovery over 70 years ago, mechanisms used by the pathogen to parasitize host cells remain poorly understood. During infection, C. burnetii actively regulates multiple host processes, including vesicular trafficking and cell survival. The bacterial proteins mediating these events are not known but are likely delivered to the host cytosol by a Dot/Icm type IV secretion system. The current application is designed to functionally characterize C. burnetii plasmid-encoded Dot/Icm substrates and define their role in virulence. All C. burnetii isolates either harbor a large cryptic plasmid or have plasmid sequences integrated into their chromosome, suggesting these molecules are critical for pathogen biology. Interestingly, we have identified six Dot/Icm substrates encoded by C. burnetii plasmid genes that are termed Coxiella plasmid effectors A - F (CpeA - F). Three of these proteins are conserved in all isolates and three are specific to the QpH1 plasmid from a human acute disease isolate. Aim 1 is designed to characterize the interaction of conserved CpeB and CpeD with autophagosomes and secretory organelles, respectively. Aim 2 will define requirements of all six plasmid effectors during infection. Additionally, this aim will identify effector binding host proteins and determine the requirement of these components for C. burnetii infection. Aim 3 will determine the requirement of the C. burnetii plasmid for pathogen virulence in both cell culture and a guinea pig infection model of Q fever. Collectively, the aims in the current application will provide needed insight into the mechanisms used by C. burnetii to efficiently parasitize host cells. These studies will also provide novel information regarding the role of the C. burnetii cryptic plasmid in pathogen virulence.

描述（由申请人提供）：伯内特立克次体是一种细胞内细菌病原体，也是人类 Q 热的病原体，Q 热是一种急性衰弱性流感样疾病，可进展为慢性心内膜炎。自 70 多年前被发现以来，人们对病原体寄生宿主细胞的机制仍知之甚少。在感染过程中，伯氏念珠菌积极调节多个宿主过程，包括囊泡运输和细胞存活。介导这些事件的细菌蛋白尚不清楚，但很可能通过 Dot/Icm IV 型分泌系统递送至宿主细胞质。当前的应用旨在对伯内特梭菌质粒编码的 Dot/Icm 底物进行功能表征，并确定其在毒力中的作用。所有伯氏念珠菌分离株要么含有一个大的隐性质粒，要么将质粒序列整合到其染色体中，这表明这些分子对于病原体生物学至关重要。有趣的是，我们已经鉴定了由伯氏梭菌质粒基因编码的六种 Dot/Icm 底物，这些底物被称为柯克斯体质粒效应子 A - F (CpeA - F)。其中 3 个蛋白在所有分离株中都是保守的，其中 3 个是人类急性疾病分离株的 QpH1 质粒特异的。目标 1 旨在表征保守的 CpeB 和 CpeD 分别与自噬体和分泌细胞器的相互作用。目标 2 将定义感染期间所有六种质粒效应器的要求。此外，该目标将鉴定效应子结合宿主蛋白并确定伯内特衣藻感染对这些成分的需求。目标 3 将确定细胞培养物和 Q 热豚鼠感染模型中病原体毒力对伯内特衣原体质粒的要求。总的来说，当前应用的目标将提供对 C. burnetii 有效寄生宿主细胞的机制所需的深入了解。这些研究还将提供有关伯内特隐孢子虫隐性质粒在病原体毒力中的作用的新信息。

项目成果

Dot/Icm type IVB secretion system requirements for Coxiella burnetii growth in human macrophages.

• DOI: 10.1128/mbio.00175-11
• 发表时间: 2011
• 期刊: mBio
• 影响因子: 6.4
• 作者: Beare PA;Gilk SD;Larson CL;Hill J;Stead CM;Omsland A;Cockrell DC;Howe D;Voth DE;Heinzen RA
• 通讯作者: Heinzen RA

ThANKs for the repeat: Intracellular pathogens exploit a common eukaryotic domain.

感谢重复：细胞内病原体利用共同的真核结构域。

• DOI: 10.4161/cl.1.4.18738
• 发表时间: 2011
• 期刊: Cellular logistics
• 作者: Voth,DanielE