Epidemic Typhus Pathogenesis

流行性斑疹伤寒发病机制

• 批准号: 7738755
• 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: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7738755
• 关键词: Address; Aerosols; Animal Model; Animals; Antibiotics; Applications Grants; Attenuated; Biological Assay; Biological Warfare; Blood Vessels; Brill' s Disease; C3H/HeN Mouse; Categories; Cell Adhesion Molecules; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Citrate (si)-Synthase; Development; Disease; Disease Outbreaks; Dose; Economic Conditions; Economics; Electroporation; Endothelial Cells; Endothelium; Enzyme-Linked Immunosorbent Assay; Epidemic; Epidemiology; Famines; Feces; Fever; Foundations; Functional disorder; Genome; Genomics; Geographic Locations; Gram-Negative Bacteria; Host Defense; Human; Human body; Hygiene; Immune response; Immunocompetent; Immunologics; Immunoprecipitation; In Vitro; Inbred BALB C Mice; Infection; Inflammation; Intercellular adhesion molecule 1; Interferons; Intervention; Intravenous; Investigation; JUN gene; Jail; Kidney; Kinetics; Knowledge; Laboratories; Laboratory mice; Lead; Lethal Dose 50; Lice; Liver; Luciferases; Lung; MAP Kinase Signaling Pathways; MAPK14 gene; Measurement; Measures; Metabolic; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Modeling; Molecular; Monocyte Chemoattractant Protein-1; Morbidity - disease rate; Mouse Strains; Movement; Mus; NF-kappa B; National Institute of Allergy and Infectious Disease; Nuclear; Pathogenesis; Pathologic; Pathway interactions; Patients; Pediculus humanus humanus; Phosphorylation; Phosphotransferases; Plasma; Predisposition; Proteins; Proteomics; Recording of previous events; Refugees; Reporting; Research; Rickettsia; Rickettsia Infections; Rickettsia prowazekii; Route; Serum; Signal Pathway; Signal Transduction; Site; Spleen; Stress; TNFRSF5 gene; Testis; Tissues; Transcriptional Activation; Typhus; Vascular Endothelial Cell; Vascular Endothelium; Virulence; Virulence Factors; Virulent; War; World War I; base; brain tissue; cell type; chemokine; combat; comparative; cytokine; design; disease transmission; efficacy testing; enzyme activity; genetic manipulation; human disease; in vitro testing; in vivo; in vivo Model; infancy; mitogen-activated protein kinase p38; mortality; mouse model; novel; novel therapeutics; p65; pathogen; promoter; prototype; public health relevance; research study; response; transcription factor; transmission process; vaccine candidate; vascular inflammation; von Willebrand Factor

DESCRIPTION (provided by applicant): Epidemic typhus, also known as Gaol fever, Jail fever, or Famine fever, is caused by the Gram-negative bacterium Rickettsia prowazekii. This louse-borne disease has been responsible for devastating widespread epidemics throughout history, especially during and after the wars, famine, and poor socio-economic conditions, and is the only known rickettsiosis that can recur after a long period of latency (Brill-Zinsser disease). R. prowazekii is classified as a CDC/NIAID Category B biological warfare pathogen, the entire genome for which was the first to be sequenced among all known Rickettsia species. Although tremendous strides have recently been made in the genetic manipulation of R. prowazekii, the knowledge of molecular aspects of interactions with the vascular endothelium, the preferred cell type infected during human infections, still remains in its infancy. Endothelial cells, key immunoreactive cells involved in host defense and inflammation, are also intimately involved in the manifestations of rickettsial infections. On the basis of interactions of host endothelial cells with R. prowazekii and R. typhi (the etiologic agent of endemic typhus), we have identified activation of nuclear factor kappa B (NF-?B) and stress-activated p38 protein kinase as critically important regulatory signaling mechanisms that contribute to host cell activation and responses to infection. Specific Aim 1 of this exploratory grant application is designed to define the intensity and kinetics of the activation of NF-?B and MAP kinase signaling pathways after R. prowazekii infection of vascular endothelial cells in vitro and test the hypothesis that potential differences in intracellular signaling mechanisms determine the intensity of host cell activation in response to virulent Breinl versus attenuated Madrid E versus virulent revertant Evir strains of R. prowazekii. Aim 2 will focus on establishing and characterizing a mouse model of R. prowazekii infection that closely mimics the major pathological features, i.e. disseminated endothelial infection and vascular inflammation, of epidemic typhus disease in humans. Taken together, these studies will address critical gaps in our current understanding of in vitro and in vivo interactions between vascular endothelium and R. prowazekii and mechanisms underlying 'endothelial activation' during typhus rickettsioses. The long-term objective of this project is to establish the foundation for comprehensive understanding of epidemic typhus pathogenesis by identifying specialized vascular cell signaling pathways activated in vitro and subsequent detailed analysis of their involvement in determination of innate and adaptive immune responses with an aim to develop unique chemotherapeutic strategies focused at targeted intervention. In addition, detailed characterization of a small animal model of infection akin to disease in humans will allow us to define unique features of virulence factors and pathogenesis of epidemic typhus, to expand our understanding of in vivo immune responses, and to test the efficacy of novel antibiotics and vaccine candidates. PUBLIC HEALTH RELEVANCE: Typhus epidemics due to louse-borne Rickettsia prowazekii have caused more deaths than all the wars combined and recent epidemiological evidence documents the reemergence of epidemic typhus in different geographic locations of the world. Since vascular dysfunction and damage are the major pathologic sequelae responsible for complications of human rickettsial diseases, obtaining a definition of signaling interactions between host endothelial cells and R. prowazekii strains of varying virulence and detailed characterization of a mouse model of disseminated infection of the vasculature represent first major steps in advancing our understanding of pathogenesis of epidemic typhus, which will ultimately lead to the development of novel therapeutic and immunologic strategies to combat this debilitating rickettsial disease.

描述（由申请人提供）：流行性斑疹伤寒，也称为监狱热、监狱热或饥荒热，是由革兰氏阴性细菌普瓦泽基立克次体引起的。这种虱子传播的疾病在历史上一直造成毁灭性的广泛流行，特别是在战争、饥荒和恶劣的社会经济条件期间和之后，并且是唯一已知的立克次体病，可以在长时间潜伏期后复发（布里尔-津瑟病）。普瓦泽基立克次体被归类为 CDC/NIAID B 类生物战病原体，其整个基因组是所有已知立克次体物种中第一个被测序的。尽管最近在普罗瓦泽基菌的基因操作方面取得了巨大进步，但对与血管内皮（人类感染期间优选的感染细​​胞类型）相互作用的分子方面的了解仍处于起步阶段。内皮细胞是参与宿主防御和炎症的关键免疫反应细胞，也与立克次体感染的表现密切相关。基于宿主内皮细胞与普罗瓦兹基菌和伤寒菌（地方性斑疹伤寒的病原体）的相互作用，我们发现核因子κB（NF-κB）的激活和应激激活的p38蛋白激酶是至关重要的调节信号机制，有助于宿主细胞激活和对感染的反应。本次探索性拨款申请的具体目标 1 旨在定义普罗瓦泽基菌体外感染血管内皮细胞后 NF-κB 和 MAP 激酶信号通路激活的强度和动力学，并测试以下假设：细胞内信号传导机制的潜在差异决定了宿主细胞对强毒 Breinl 与减毒马德里 E 与强毒回复回复体的反应强度 R. prowazekii 的 Evir 菌株。目标 2 将重点建立和表征普罗瓦泽基菌感染的小鼠模型，该模型密切模拟人类流行性斑疹伤寒的主要病理特征，即播散性内皮感染和血管炎症。总而言之，这些研究将解决我们目前对血管内皮和普氏立克次氏体之间的体外和体内相互作用以及斑疹伤寒立克次体病期间“内皮激活”潜在机制的理解中的关键差距。该项目的长期目标是通过鉴定体外激活的专门血管细胞信号通路，并随后详细分析它们在确定先天性和适应性免疫反应中的参与，为全面了解流行性斑疹伤寒发病机制奠定基础，旨在开发专注于靶向干预的独特化疗策略。此外，对类似于人类疾病的小动物感染模型的详细表征将使我们能够定义流行性斑疹伤寒的毒力因子和发病机制的独特特征，扩大我们对体内免疫反应的理解，并测试新型抗生素和候选疫苗的功效。公共卫生相关性：由虱子传播的普氏立克次体引起的斑疹伤寒流行造成的死亡人数比所有战争造成的死亡人数总和还多，最近的流行病学证据表明流行性斑疹伤寒在世界不同地理位置重新出现。由于血管功能障碍和损伤是导致人类立克次体疾病并发症的主要病理后遗症，因此获得宿主内皮细胞和不同毒力的普氏立克次体菌株之间信号相互作用的定义以及脉管系统播散性感染小鼠模型的详细表征代表了推进我们对流行性斑疹伤寒发病机制的理解的第一个重要步骤，这将最终导致 开发新的治疗和免疫策略来对抗这种使人衰弱的立克次体病。