Exploring Tr1-regulated transcription networks underpinning adaptation of pathogenic Anaplasma to the tick host

探索 Tr1 调节的转录网络支持致病性无形体对蜱宿主的适应

基本信息

批准号：
10727435
负责人：
Jason Michael Park
金额：
$ 21.54万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10727435
关键词：
Anaplasma Anaplasma phagocytophilum Animals Architecture Arthropod Vectors Arthropods Attenuated Bacteria Binding Bioinformatics Biology Body Temperature Cell Culture Techniques Cell Survival Cells Cues DNA DNA Binding DNA Binding Domain DNA Sequence DNA-Binding Proteins Dependence Development Disease Disparate Disparity Environment Evolution Face Family Gene Expression Genes Genetic Transcription Genome Genomics Growth Helix-Turn-Helix Motifs Homologous Gene Human Human Cell Line Immunologics Infection Intervention Lead Life Cycle Stages Life Style Livestock Mammalian Cell Mammals Measures Modeling Mus Mutate Mutation Nutrient availability Operon Pathogenicity Pattern Physiological Proteins Regulon Repression Research Response Elements Rickettsia Role Side Stimulus Structural Models Testing Tick-Borne Diseases Ticks Transcriptional Regulation United States Vector-transmitted infectious disease Work Xenobiotics disease transmission gene network genetic regulatory protein innovation mutant pathogen pathogenic bacteria physical property pressure response tick-borne transcription factor transcriptome transmission process vector vector transmission vector-borne vector-borne pathogen

项目摘要

Project Summary Tick-borne diseases are on the increase and are responsible for nearly all of the vector-transmitted disease in the US. Vector-borne pathogens face the dual challenge of adaptation to two very different host environments: the arthropod vector and the mammalian host. Ticks contain distinct physiological cues including disparities in body temperature, nutrient availability, physiological architecture, and unique immunological pressures. Once in the tick, A. phagocytophilum must further adapt to construct a replicative niche within the arthropod’s cells. In response to the tick environment, A. phagocytophilum differentially transcribes 41% of its genes when infecting tick cells in comparison to mammalian cell culture. It is not known what controls this extensive reprogramming or how it facilitates A. phagocytophilum adaptation to the tick. One predicted transcription factor, tr1, displays the highest tick-specific expression of all A. phagocytophilum genes. Our structural modeling identifies Tr1 as a homo-dimeric helix-turn-helix DNA binding protein in the xenobiotic response element family of transcription factors. Disruption of tr1 by transposon insertion had no impact on bacterial burden in mice or growth in human cell lines. However, A. phagocytophilum lacking tr1 was greatly attenuated for acquisition by ticks and is unable to survival in tick cells. Given the importance of Tr1 for survival in the arthropod vector and its predicted role as a transcriptional switch, we hypothesize that: Tr1 operates as a master regulator for tick adaptation by orchestrating the expression of tick-specific gene networks. In this study we will identify the DNA sequences bound by Tr1 and its mode of transcription regulation. Further, we will identify how Tr1 contributes to completion of the tick cell infection cycle and measure how Tr1 remodels the A. phagocytophilum transcriptome during tick cell infection. Revealing how A. phagocytophilum adapts to infect tick cells will open the door to development of vector targeted interventions to reduce transmissibility of the pathogen.

项目概要蜱传疾病呈上升趋势，几乎是所有媒介传播疾病的罪魁祸首在美国，媒介传播的病原体面临着适应两种截然不同的宿主的双重挑战。环境：节肢动物媒介和哺乳动物宿主具有不同的生理线索。包括体温、营养可用性、生理结构和独特的差异一旦进入蜱体内，嗜吞噬细胞菌必须进一步适应以构建复制体。节肢动物细胞内的生态位对蜱环境的反应不同。与哺乳动物细胞培养物相比，感染蜱细胞时转录其基因的 41%。是什么控制着这种广泛的重编程，或者它如何促进嗜吞噬细胞适应蜱。预测的转录因子 tr1 在所有嗜吞噬细胞曲霉基因中表现出最高的蜱特异性表达。我们的结构模型将 Tr1 识别为异生物质中的同源二聚体螺旋-转角-螺旋 DNA 结合蛋白转座子插入对转录因子反应元件家族的破坏没有影响。然而，缺乏 tr1 的 A. phagocytophilum 会显着降低小鼠体内的细菌负担或人类细胞系的生长。考虑到 Tr1 对生存的重要性，蜱虫获得的 Tr1 被减弱，并且无法在蜱细胞中存活。在节肢动物载体及其作为转录开关的预测作用中，我们发现： Tr1 作为转录开关发挥作用在这项研究中，通过协调蜱特异性基因网络的表达来调节蜱的适应。我们将鉴定Tr1结合的DNA序列及其转录调控模式。确定 Tr1 如何有助于完成蜱细胞感染周期并测量 Tr1 如何重塑 A. 揭示蜱细胞感染过程中的吞噬细胞转录组。蜱细胞将为开发载体靶向干预措施打开大门，以减少蜱虫的传播性病原。