Notch signaling and functional relevance during Ehrlichia chaffeensis infection

恰菲埃里希体感染期间的Notch信号传导和功能相关性

• 批准号: 9316270
• 负责人: JERE W MCBRIDE
• 金额: $ 22.92万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-05 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316270
• 关键词: Affect; Agonist; Apoptosis; Autophagocytosis; Bacteria; Binding; Cell Proliferation; Cell Survival; Cell physiology; Cell surface; Cells; Complex; Cytoskeletal Modeling; DNA; Development; Down-Regulation; Ehrlichia; Ehrlichia chaffeensis; Ehrlichiosis; Elements; Etiology; FBXW7 gene; FRAP1 gene; Feasibility Studies; Gene Targeting; Genes; Genetic Transcription; Goals; Host Defense; Human; Immune; Immune response; Infection; Inflammatory; Inflammatory Response; Investigation; Knowledge; Life; Link; Mediating; Metalloproteases; Microbe; Molecular; Mononuclear; Notch Signaling Pathway; Pathway interactions; Pattern Recognition; Pattern recognition receptor; Phagocytes; Play; Post-Translational Protein Processing; Production; Proteins; Receptor Signaling; Regulation; Research Project Grants; Role; Signal Pathway; Signal Transduction; System; TLR2 gene; TLR4 gene; Tandem Repeat Sequences; Tertiary Protein Structure; Testing; Therapeutic; Ticks; Toll-like receptors; Transcriptional Regulation; Translational Regulation; United States; Virulence Factors; adaptive immune response; antimicrobial; cell growth; cytokine; genetic regulatory protein; insight; knock-down; monocyte; notch protein; novel; novel therapeutic intervention; novel therapeutics; pathogen; programs; receptor expression; small molecule; trafficking; transcription factor

Project Summary Ehrlichia chaffeensis is a gram-negative, obligately intracellular bacterium that is the causative agent of human monocytotropic ehrlichiosis (HME), an emerging life-threatening tick-borne zoonosis. A major knowledge gap is in our understanding of the mechanisms whereby E. chaffeensis establishes intracellular infection of the mononuclear phagocyte and avoids innate host defenses. We recently demonstrated that E. chaffeensis utilizes a type 1 secretion (T1S) system to export tandem repeat protein (TRP) effectors that interact with host cell DNA and a functionally diverse array of host proteins involved in transcriptional and translational regulation, post translational modification, signaling, immune response, intracellular trafficking, cytoskeletal organization and apoptosis. Two TRP120 interacting host proteins include the Notch activating metalloprotease ADAM17, and the negative regulator, FBW7. Notch is a highly conserved eukaryotic signaling pathway that plays a key role in determining cell growth, differentiation and function, which extends to immune cells. Recent studies have identified a functional relationship between the Notch pathway and negative regulation of toll-like receptor (TLR)-mediated immune responses and autophagy, both of which are suppressed during E. chaffeensis infection. Preliminary studies that serve as the basis for this proposal demonstrate that E. chaffeensis activates canonical Notch signaling pathway to promote survival. Activation of this pathway promotes ehrlichial survival by downregulating PU.1 (transcription factor required for TLR2/4 expression) and TLR expression, and by inhibiting of lysosomal fusion and autophagic degradation. The objective of this proposal is to determine the role of Ehrlichia TRPs in Notch pathway activation, and to demonstrate TRP-induced Notch-mediated modulation of PRR expression and autophagy. We hypothesize E. chaffeensis activates the Notch pathway through molecular interactions between TRP effectors and the Notch receptor complex to initiate a prosurvival cell signaling program that suppresses innate defenses. We will test this hypothesis with the following specific aims: (1) Determine the effect of E. chaffeensis induced Notch signaling on innate host defenses; (2) Define the mechanism of E. chaffeensis TRP-mediated Notch pathway activation and regulation. This investigation will expand our knowledge regarding exploitation of highly conserved host cell pathways by E. chaffeensis effectors in order to facilitate bacterial intracellular survival. Moreover, new targets for the development of novel therapeutic approaches against E. chaffeensis infection will be identified.

项目摘要 Ehrlichia chaffeensis是一种革兰氏阴性菌，有规律的细胞内细菌，是人类的病因 单核细胞性ehrlichiosis（HME），这是一种新兴的威胁生命的tick虫动物动物。一个主要的知识差距是 在我们对谷链球菌建立细胞内感染的机制的理解中 单核吞噬细胞并避免先天的宿主防御能力。我们最近证明了Chaffeensis 利用1型分泌（T1S）系统导出与主机相互作用的串联重复蛋白（TRP）效应子 细胞DNA以及参与转录和翻译的功能多样的宿主蛋白 调节，翻译后修饰，信号传导，免疫反应，细胞内运输，细胞骨架 组织和凋亡。两种TRP120相互作用的宿主蛋白包括Notch激活 金属蛋白酶ADAM17和负调节剂FBW7。 Notch是高度保守的真核信号 在确定细胞生长，分化和功能中起关键作用的途径，该途径延伸至免疫 细胞。最近的研究已经确定了Notch途径与负面的功能关系 调节Toll样受体（TLR）介导的免疫反应和自噬的调节，这两种反应都是 在大肠杆菌感染期间被抑制。作为该提案的基础的初步研究 证明Chaffeensis激活规范凹口信号传导途径以促进生存。激活 该途径通过下调PU.1（TLR2/4所需的转录因子 表达）和TLR表达，并通过抑制溶酶体融合和自噬降解。这 该建议的目的是确定ehrlichia trps在Notch途径激活中的作用，并确定 证明了TRP诱导的Notch介导的PRR表达和自噬的调节。我们假设 E. Chaffeensis通过TRP效应子与 Notch受体复合物启动了抑制先天防御的Prosurvival细胞信号传导程序。我们 将以以下特定目的检验该假设：（1）确定Chaffeensis诱导的效果 先天宿主防御措施的Notch发出信号； （2）定义Chaffeensis trp介导的Notch的机制 途径激活和调节。这项调查将扩大我们有关剥削的知识 Chaffeensis效应子保守的宿主细胞途径，以促进细菌细胞内存活。 此外，开发针对Chaffeensis感染的新型治疗方法的新目标 将被确定。