Wnt signaling during Ehrlichia infection

埃里希体感染期间的 Wnt 信号传导

• 批准号: 9167858
• 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: 2016
• 资助国家: 美国
• 起止时间: 2016-06-16 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9167858
• 关键词: Autophagocytosis; Bacteria; Bacterial Infections; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Data; Development; Disease; Ehrlichia; Ehrlichia chaffeensis; Ehrlichiosis; Feasibility Studies; Feedback; Gene Proteins; Gene Targeting; Genetic Transcription; Goals; Growth; Host Defense; Human; Immune response; Indium; Infection; Inflammation; Invaded; Investigation; Knowledge; Life; Mediating; Microbe; Modeling; Molecular; Molecular Target; Mononuclear; Oncogenic; Organism; Pathogenesis; Pathway interactions; Phagocytes; Phagocytosis; Process; Proteins; Recruitment Activity; Regulation; Research Project Grants; Role; Salmonella; Signal Pathway; Signal Transduction; Tandem Repeat Sequences; Therapeutic; Ticks; Zoonoses; antimicrobial; cofactor; genetic regulatory protein; human disease; insight; killings; knock-down; microbial; novel; novel therapeutics; pathogen; prevent; programs; receptor; therapeutic target

Ehrlichia chaffeensis is a gram-negative obligately intracellular bacterium and the etiologic agent of human monocytotropic ehrlichiosis (HME), an emerging life-threatening tick-borne zoonosis. E. chaffeensis utilizes a class of type 1 secreted (T1S) exoproteins, the tandem repeat protein (TRP) effectors, to facilitate internalization and promote intracellular survival. TRP genes are highly expressed during infection of mammalian hosts, and are involved in diverse interactions with host target proteins including components of Wnt signaling pathways. Wnt signaling, typically studied in the context of development, oncogenic growth, and inflammation, is known to influence cell proliferation, differentiation, phagocytosis, and autophagy. Ehrlichia TRP32 and TRP120 interact with host transcription cofactors and components of feedback pathways that regulate Wnt signaling. We have determined that E. chaffeensis upregulates Wnt-mediated gene transcription, and inhibition or knockdown of components of canonical and non canonical Wnt pathways prevents E. chaffeensis entry and survival. The long-term goal of this research project is to understand the role of the Wnt pathway in E. chaffeensis infection and intracellular survival. The objective of this proposal is to determine the mechanisms through which Ehrlichia induce Wnt pathway activation and the functional implications related to bacterial internalization and intracellular survival. We hypothesize that E. chaffeensis activates the Wnt canonical and non canonical pathways via T1S TRP effector-host interactions to induce phagocytosis, intracellular survival through suppressing autophagy. In aim 1, we will characterize E. chaffeensis activation of Wnt pathways, and the functional implications for bacterial infection and survival. Aim 2 will identify the pathogen-host interactions involved in E. chaffeensis-induced Wnt activation, and the role of the ehrlichial TRP effectors in modulating Wnt signaling. Targeting of Wnt signaling by Ehrlichia for the purpose of entry and survival provides an excellent model in which to investigate microbial molecular and cellular manipulation of these pathways. Our study will provide insight into cellular/molecular network-altering strategies utilized by these intracellular pathogens to gain access to host cells and avoid killing mechanisms. Understanding the significance of the interaction between E. chaffeensis TRPs and host Wnt pathways will contribute to our broader knowledge of bacterial effectors, the context in which these effectors function, and further define their molecular functional roles as moonlighting effectors. We expect that knowledge gained through this investigation will also contribute to the identification of new molecular targets for development of alternative antimicrobial therapeutics.

查菲埃里希菌是一种革兰氏阴性的胞内专性细菌，是人类 单核细胞增生性埃立克体病(HME)，一种新出现的威胁生命的人畜共患病。查菲乳杆菌利用一种 一类分泌的1型(T1S)外源蛋白，串联重复蛋白(Trp)的效应物，以促进 内化并促进细胞内生存。Trp基因在感染过程中高度表达 哺乳动物宿主，参与与宿主靶蛋白的多种相互作用，包括 WNT信号通路。WNT信号，通常在发育、致癌生长和 炎症，已知会影响细胞的增殖、分化、吞噬和自噬。埃里希菌 TRP32和TRP120与宿主转录辅因子和反馈通路组件相互作用 调节WNT信号。我们已经确定查菲埃希氏菌上调Wnt介导的基因转录， 抑制或敲除规范和非规范Wnt途径的成分可阻止E. 查菲斯的进入和生存。这项研究项目的长期目标是了解WNT的作用 查菲肠杆菌感染与细胞内存活的途径。这项建议的目标是确定 埃立克体诱导Wnt途径激活的机制及其功能意义 细菌内化和细胞内生存。我们假设查菲肠杆菌激活了Wnt 通过T1S色氨酸效应器-宿主相互作用诱导吞噬的规范和非规范途径， 通过抑制自噬在细胞内存活。在目标1中，我们将表征查菲肠杆菌的活性。 WNT途径，以及细菌感染和生存的功能含义。目标2将确定 病原菌-宿主相互作用参与查菲埃希氏菌诱导的Wnt激活，以及埃利西里色氨酸蛋白的作用 调节Wnt信号的效应器。埃立克体靶向Wnt信号以进入和 存活提供了一个很好的模型，在其中研究微生物分子和细胞操作 这些小路。我们的研究将为人们利用细胞/分子网络改变策略提供见解 这些细胞内的病原体能够进入宿主细胞并避免杀伤机制。了解 查菲乳杆菌TRPs与寄主Wnt途径相互作用的意义将有助于我们的 关于细菌效应器的更广泛的知识，这些效应器发挥作用的上下文，并进一步定义它们的 作为兼职效应器的分子功能作用。我们希望通过这种方式获得的知识 调查还将有助于确定开发替代药物的新分子靶标。 抗菌疗法。