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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.

项目总结