Modulation of Host Cell Apoptosis By Pathogenic Rickettsiae

致病性立克次体对宿主细胞凋亡的调节

• 批准号: 7211768
• 负责人: Sanjeev K. Sahni
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211768
• 关键词: Actins; Address; Affect; Anaplasma; Apoptosis; Apoptosis Promoter; Apoptotic; Applications Grants; Arts; Bacteria; Bacterial Infections; Bartonella; Behavior; Biochemical; Blood Vessels; Caspase; Categories; Cell Death; Cell Line; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Child; Chlamydia; Class; Clinical; Coagulants; Complex; Cytolysis; Cytoplasm; Data; Development; Disease Outcome; Elderly; Endothelial Cells; Ensure; Environment; Epidemic; Equilibrium; Event; Family; Fever; Gene Proteins; Genes; Genetic; Genomics; Geographic Locations; Growth; Host Defense; Host Defense Mechanism; Human; In Vitro; Infection; Inflammatory; Invaded; Kinetics; Knowledge; Laboratories; Life; Maintenance; Mediating; Microscopic; Mitochondria; Molecular; Molecular Genetics; NF-kappa B; Necrosis; Numbers; Organism; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Prevention; Property; Proteins; Proteomics; Regulation; Research Personnel; Resistance; Rickettsia; Rickettsia Infections; Rocky Mountain Spotted Fever; Scourge; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Spottings; Staging; Stimulus; TP53 gene; Tail; Testing; Time; Typhus; Vascular Endothelium; base; cell motility; comparative; cytotoxicity; design; disability; human MAPK14 protein; improved; insight; interest; microbial; microorganism; novel; pathogen; pathogenic bacteria; programs; research study; response; vascular inflammation

DESCRIPTION (provided by applicant): The obligate intracellular bacteria belonging to Rickettsia species are etiological agents of the spotted fever and typhus groups (SFG and TG) of rickettsial diseases in almost all geographic locations worldwide. Rocky Mountain spotted fever and epidemic typhus, caused respectively by R. rickettsii and R. prowazekii, are serious infections that can be fatal in children, elderly, and immunodeficient or misdiagnosed/untreated patients. A major clinical hallmark is the infection of endothelial cell lining of vessels, ultimately leading to vascular inflammation and damage. While apoptosis serves as an important host defense mechanism to restrict proliferation and ensuing pathogenesis during bacterial infections, intracellular rickettsiae require intimate association with the target host cells for their growth/spread. It is thus possible that like other intracellular pathogens, rickettsiae may also utilize strategies to inhibit host apoptosis early during the infection for sake of their own survival. Identified and described by our laboratory, one such strategy during endothelial cell infection of R. rickettsii is the activation of NF-?B, but nothing is known about cell signaling events during infection with and potential anti-apoptotic activities of typhus group organisms. To address this critical gap in the existing knowledge of rickettsial pathogenetic mechanisms is highly significant because of distinctive differences in the intracellular behavior of SFG and TG organisms and the potential for intentional use of R. prowazekii (Class B on CDC list) and R. rickettsii (Category C) as bioterror agents. The objectives of this exploratory grant application are to investigate the hypothesis that early during the infection, rickettsiae trigger anti-apoptotic mechanism(s) in host cells to facilitate the establishment and progression of infection and to define potential similarities or differences in host signaling mechanisms exploited by SFG and TG rickettsiae by conducting simultaneous and thorough comparative analyses. Aim 1 is designed to identify apoptotic and anti-apoptotic signaling pathways induced by representative Rickettsia species and will focus on 'shift(s)' in the equilibrium between pro- and anti-apoptotic genes and proteins of Bcl-2, IAP, and p53 families. Aim 2 will further decipher the complex mechanistic aspects of apoptosis regulation during Rickettsia infection by discerning the involvement of extrinsic or intrinsic cascades and identifying the upstream initiator and downstream effector caspases. Employing a combination of conventional biochemical and state of the art microscopic/molecular genetic approaches, we will reveal novel insights into the molecular basis of Rickettsiae-mediated modulation of apoptosis and improve our understanding of the unique perspective of manipulation of host functions by parasitic intracellular pathogens. Acquisition of this new knowledge regarding adaptations in host cell signaling and recent progress in the genomic and proteomic characterization of Rickettsia organisms will enable us to identity and isolate potential rickettsial anti-apoptotic activity(ies), which can be targeted to develop new and improved strategies aimed at enhancing clearance of infected cells early to avoid disseminated endothelial infection and associated vascular pathologies.

描述（由申请人提供）：属于立克次体属的专性细胞内细菌是全球几乎所有地理位置的立克次体疾病的斑点热和斑疹伤寒群（SFG和TG）的病原体。落基山斑疹热和流行性斑疹伤寒分别由罗氏立克次体引起。rickettsii和R.普氏疟原虫是严重的感染，在儿童、老年人和免疫缺陷或误诊/未治疗的患者中可能是致命的。一个主要的临床标志是血管内皮细胞衬里的感染，最终导致血管炎症和损伤。虽然细胞凋亡作为一种重要的宿主防御机制，以限制增殖和随后的发病机制，在细菌感染，细胞内立克次体需要与靶宿主细胞的密切联系，他们的生长/传播。因此，像其他细胞内病原体一样，立克次体也可能利用策略在感染早期抑制宿主细胞凋亡，以维持自身的生存。本实验室发现并描述了一种在内皮细胞感染R.立克次氏体是NF-？B，但对斑疹伤寒组生物体感染期间的细胞信号传导事件和潜在的抗凋亡活性一无所知。为了解决这个关键的差距，在现有的知识立克次体的致病机制是非常重要的，因为显着的差异，在细胞内行为的SFG和TG生物体和潜在的有意使用的R。prowazekii（CDC分类B类）和R.立克次氏体（C类）作为生物恐怖剂。这项探索性资助申请的目的是调查这一假设，即在感染早期，立克次体触发宿主细胞中的抗凋亡机制，以促进感染的建立和进展，并通过同时进行全面的比较分析，确定SFG和TG立克次体利用的宿主信号传导机制的潜在相似性或差异。目的1旨在确定由代表性立克次体物种诱导的凋亡和抗凋亡信号通路，并将关注Bcl-2，IAP和p53家族的促凋亡和抗凋亡基因和蛋白质之间的平衡的“转变”。目的2将通过识别外源性或内源性级联反应的参与，并确定上游启动子和下游效应子半胱天冬酶，进一步解释立克次体感染过程中细胞凋亡调控的复杂机制。采用传统的生物化学和最先进的显微镜/分子遗传学方法相结合，我们将揭示新的见解立克次体介导的细胞凋亡的调制的分子基础，提高我们的理解的独特视角操纵宿主功能的寄生性细胞内病原体。获得关于宿主细胞信号转导适应性的新知识以及立克次体生物体基因组和蛋白质组学表征的最新进展将使我们能够识别和分离潜在的立克次体抗凋亡活性，这可以有针对性地开发新的和改进的策略，旨在早期增强感染细胞的清除，以避免播散性内皮感染和相关的血管病变。