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

基本信息

批准号：
9408616
负责人：
JERE W MCBRIDE
金额：
$ 19.05万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-05 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9408616
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

项目摘要

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.

项目概要恰菲埃里希体是一种革兰氏阴性、专性细胞内细菌，是人类肺炎的病原体单核细胞嗜埃利希体病（HME），一种新出现的危及生命的蜱传人畜共患病。主要的知识差距是在我们对查菲埃里希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宿主防御。我们最近证明了查菲埃里希菌利用 1 型分泌 (T1S) 系统输出与宿主相互作用的串联重复蛋白 (TRP) 效应子细胞 DNA 和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、细胞骨架组织和细胞凋亡。两个 TRP120 相互作用的宿主蛋白包括 Notch 激活蛋白金属蛋白酶 ADAM17 和负调节因子 FBW7。 Notch是一种高度保守的真核信号传导在决定细胞生长、分化和功能方面发挥关键作用的途径，延伸至免疫细胞。最近的研究已经确定了 Notch 通路与负信号之间的功能关系。 Toll 样受体 (TLR) 介导的免疫反应和自噬的调节，两者都是查菲埃里希菌感染期间受到抑制。作为本提案基础的初步研究证明查菲埃里希菌激活典型的 Notch 信号通路以促进生存。激活该途径通过下调 PU.1（TLR2/4 所需的转录因子）促进埃利希体存活表达）和 TLR 表达，并通过抑制溶酶体融合和自噬降解。这该提案的目的是确定埃里希体 TRP 在 Notch 通路激活中的作用，并证明 TRP 诱导的 Notch 介导的 PRR 表达和自噬调节。我们假设查菲埃里希菌通过 TRP 效应子和 Notch 受体复合物启动抑制先天防御的促存活细胞信号传导程序。我们将通过以下具体目标来检验这一假设： (1) 确定查菲埃里希菌诱导的效果先天宿主防御上的Notch信号传导； (2) 明确查菲埃里希菌TRP介导的Notch机制途径激活和调节。这项调查将扩大我们对高度开发利用的认识查菲埃里希菌效应子保守的宿主细胞途径，以促进细菌细胞内存活。此外，开发针对查菲埃里希体感染的新治疗方法的新目标将被识别。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ehrlichia chaffeensis TRP120-mediated ubiquitination and proteasomal degradation of tumor suppressor FBW7 increases oncoprotein stability and promotes infection.

恰菲埃里希体 TRP120 介导的肿瘤抑制因子 FBW7 的泛素化和蛋白酶体降解增加了癌蛋白的稳定性并促进感染。

DOI：
发表时间：
2020-04
期刊：
影响因子：
6.7
作者：
Wang, Jennifer Y;Zhu, Bing;Patterson, LaNisha L;Rogan, Madison R;Kibler, Clayton E;McBride, Jere W
通讯作者：
McBride, Jere W