Murine Typhus

鼠型斑疹伤寒

• 批准号: 10404649
• 负责人: Mohammed Sayeedur Rahman
• 金额: $ 72.68万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404649
• 关键词: Address; Africa; Area; Arthropods; Bacteriology; Biological Assay; Biology; Boutonneuse Fever; Cell Line; Cell physiology; Cells; Central America; Clinical; Complement; Complex; Cytosol; Dependence; Disease; Disease Outbreaks; Drosophila genus; Endemic Flea-Borne Typhus; Ensure; Entomology; Epidemic; Europe; Felis catus; Fleas; Gene Expression; Gene Expression Profile; Genes; Genus Felis; Immune; Immune response; Infection; Inflammasome; Insect Vectors; Insecta; Interleukin-1 beta; Invaded; Life Cycle Stages; Light; Lipids; Longevity; Mediating; Membrane; Metabolic; Middle East; Midgut; Molecular; Molecular Genetics; Molecular and Cellular Biology; Natural Immunity; Parasites; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Peptidoglycan; Phospholipase; Physiology; Process; Public Health; Reporting; Research; Rickettsia; Rickettsia Infections; Rickettsia conorii; Rickettsia rickettsii; Rickettsia typhi; Rocky Mountain Spotted Fever; Role; Salivary Glands; South America; System; Testing; Therapeutic; Time; Tissues; Typhus; Vaccines; Virulent; Wolbachia; Work; arthropod-borne; combat; design; gene network; human pathogen; immunogenic; immunogenicity; immunoregulation; insight; interdisciplinary approach; microbiome; microbiota; mutant; novel; pathogen; pathogenic bacteria; reproductive organ; spotted fever; transmission process; vaccine access; vector

Arthropod-borne Rickettsia species are among the most virulent and lethal human pathogens and are of significant global Public Health concern. Our work over the past 3.5 years resulted in significant progress in understanding of R. typhi pathogenesis, and in particular, the role of the rickettsial secretome during host cell invasion. For this proposal, we will address fundamental questions in two understudied yet highly significant topics in rickettsial pathogen biology. First, we will determine the mechanisms by which R. typhi modulates cat flea (Ctenocephalides felis) innate immunity, microbiota and other factors to establish infection and facilitate transmission to the vertebrate host; and second, defining the functional spectrum and immunogenic potential of the R. typhi armory of secreted phospholipases that alter host membrane physiology to facilitate phagosomal escape and intracellular replication. We will implement a transdisciplinary approach (e.g., phylogenomics, bacteriology, entomology, and cellular/molecular biology) to thoroughly investigate these focal areas, as outlined by the following Specific Aims. In Aim I, we will decipher the modulatory factors R. typhi employs to colonize C. felis and facilitate transmission via 1) a robust tissue-specific, time-course expression analysis, 2) silencing IMD and Toll pathway gene expression, 3) testing the immunomodulatory propensities of isolated R. typhi peptidoglycan, and 4) characterizing the impact of the C. felis microbiome on infection. In Aim II, we will characterize the function and immunogenicity of R. typhi secretory phospholipases. We will take two approaches to characterize R. typhi phospholipases: 1) functional characterization of Pat1, Pat2 and Pld via determining their subcellular localization, lipid recognition and interactome within host cells, with downstream analyses designed to reveal the significance of these interactions in mediating bacterial access to the host cytosol; and; 2) identification of inflammasome components necessary for IL-1β secretion by R. typhi, and determining the impact of Pat1, Pat2, and Pld activities on inflammasome activation. Together these studies will significantly advance our understanding of the complex Rickettsia/vector/host relationship, shedding light on how rickettsial parasites of arthropods transition to vertebrate pathogens throughout the obligatory Rickettsia life cycle. Thus, we anticipate that our work will take us closer to generating more prudent therapeutics to combat fatal rickettsioses.

节肢动物传播的立克次体是最具毒性和致命性的人类病原体之一 我们过去 3.5 年的工作产生了重大的全球公共卫生问题。 在了解伤寒杆菌发病机制方面取得了重大进展，特别是在了解伤寒杆菌的作用方面 对于这个提议，我们将解决宿主细胞侵袭过程中的立克次体分泌体的基本问题。 立克次体病原体生物学中两个尚未得到充分研究但非常重要的主题的问题。 我们将确定伤寒杆菌调节猫蚤（Ctenocephalides felis）的机制 先天免疫、微生物群和其他因素造成感染并促进传播 脊椎动物宿主；第二，确定其功能谱和免疫原性潜力。 伤寒杆菌分泌的磷脂酶改变宿主膜生理学以促进 我们将实施跨学科的方法。 （例如，系统基因组学、细菌学、昆虫学和细胞/分子生物学）彻底 正如以下具体目标所概述的那样，我们将调查这些重点领域。 破译伤寒杆菌用于定殖猫伤寒杆菌并促进传播的调节因子 通过 1) 强大的组织特异性、时程表达分析，2) 沉默 IMD 和 Toll 途径基因表达，3) 测试分离的伤寒杆菌的免疫调节倾向 肽聚糖，4) 表征猫弯曲菌微生物组对感染的影响。 我们将表征伤寒杆菌分泌磷脂酶的功能和免疫原性。 采用两种方法来表征伤寒杆菌磷脂酶：1) Pat1 的功能表征， Pat2 和 Pld 通过确定其亚细胞定位、脂质识别和相互作用组 宿主细胞，下游分析旨在揭示这些相互作用的重要性 介导细菌进入宿主细胞质；和；2) 炎性体成分的鉴定； 伤寒杆菌分泌 IL-1β 所必需的，并确定 Pat1、Pat2 和 Pld 活性的影响 这些研究将共同​​促进我们对炎症体激活的理解。 复杂的立克次体/载体/宿主关系，揭示立克次体寄生虫如何 节肢动物在立克次体的整个生命周期中转变为脊椎动物病原体。 因此，我们预计我们的工作将使我们更接近于产生更谨慎的治疗方法 对抗致命的立克次体病。

项目成果

Genetic characterization and transovarial transmission of a typhus-like rickettsia found in cat fleas.

猫蚤中发现的斑疹伤寒样立克次体的遗传特征和跨卵巢传播。

• 发表时间: 1992-01-01
• 影响因子: 11.1
• 作者: Azad, A F;Sacci Jr, J B;Nelson, W M;Dasch, G A;Schmidtmann, E T;Carl, M
• 通讯作者: Carl, M

Detection of rickettsiae in arthropod vectors by DNA amplification using the polymerase chain reaction.

使用聚合酶链式反应通过 DNA 扩增检测节肢动物载体中的立克次体。

• 发表时间: 1990
• 影响因子: 5.2
• 作者: Azad, A F;Webb, L;Carl, M;Dasch, G A
• 通讯作者: Dasch, G A

Transovarial transmission of murine typhus rickettsiae in Xenopsylla cheopis fleas.

鼠斑疹伤寒立克次体在印鼠客蚤中的跨卵巢传播。

• 发表时间: 1985-02-01
• 作者: Farhang;Traub, R;Baqar, S
• 通讯作者: Baqar, S

Presence of calreticulin in vector fleas (Siphonaptera).

媒介跳蚤（Siphonaptera）中存在钙网蛋白。

• 发表时间: 1996-05
• 影响因子: 2.1
• 作者: Jaworski, D C;Higgins, J A;Radulovic, S;Vaughan, J A;Azad, A F
• 通讯作者: Azad, A F

Detection of point mutations in rpoB gene of rifampin-resistant Rickettsia typhi.

耐利福平伤寒立克次体rpoB基因点突变的检测

• 发表时间: 1998-07
• 影响因子: 4.9
• 作者: Troyer, J M;Radulovic, S;Andersson, S G;Azad, A F
• 通讯作者: Azad, A F