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Regulatory Role of Tandem Tryptophan Codons in Chlamydial Persistence

串联色氨酸密码子在衣原体持久性中的调节作用

基本信息

批准号：
10553272
负责人：
REY A CARABEO
金额：
$ 60.74万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-08 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553272
关键词：
Abnormal Cell Address Affect Amino Acids Anabolism Antibiotic Resistance Antigens Antimicrobial Resistance Bacteria Biological Biological Assay Biotinylation Blindness CRISPR interference Cell division Cells ChIP-seq Chlamydia Chlamydia Infections Chronic Codon Nucleotides Communication Critical Pathways Development Disease Environment Genes Genetic Transcription Genome Goals Growth Healthcare Systems Human Immune response Immunologics Indoles Infectious Agent Infertility Inflammatory Response Interferon Type II Internet Iron Label Lead Link Location Mediating Medical Membrane Proteins Messenger RNA Metabolic Modeling Molecular Molecular Chaperones Monitor Morbidity - disease rate Morphology Nature Nutrient Nutritional Organelles Organism Pathway interactions Patients Pelvic Inflammatory Disease Phenotype Physiological Pneumonia Positioning Attribute Process Protein Biosynthesis Protein Precursors Protein translocation Proteins Proteomics Regulatory Element Regulon Reiter Disease Respiratory Tract Infections Ribosomes Rickettsia Role Sampling Sexually Transmitted Diseases Starvation Stress Symptoms System Testing Therapeutic Intervention Toxin Trachoma Transcript Transcriptional Regulation Translating Translational Regulation Translations Tryptophan Type III Secretion System Pathway Vesicle Work antitoxin genetic approach human pathogen infection burden knock-down new therapeutic target novel diagnostics novel strategies pathogen pathogenic bacteria pharmacologic programs response stem therapeutic candidate transcriptome transcriptome sequencing tubal infertility

项目摘要

Project Summary: Regulatory Role of Tandem Trp Codons in Chlamydial Persistence Chlamydia is an obligate intracellular bacterial pathogen that causes a range of serious diseases in humans. It is the primary cause of bacterial sexually transmitted infections (STI) and the causative agent of infectious preventable blindness, trachoma. The major concern of chlamydial infections is that they are often asymptomatic and undiagnosed, which can lead to chronic sequelae, such as pelvic inflammatory disease and tubal factor infertility. Consequently, chlamydial diseases remain a significant burden on health care systems around the world. In adapting to obligate intracellular growth, Chlamydia has significantly reduced its genome size and eliminated genes from various pathways as it relies on the host cell for its metabolic needs. Most bacteria respond to amino acid limitation by engaging a stringent response, which is a transcriptional program used to adapt to nutrient-poor conditions. The stringent response has also been directly connected with inducing persister cells in various types of bacteria, which have limited metabolic activity and increased antimicrobial resistance. Chlamydia can become persistent when limited for nutrients such as tryptophan (trp). They are morphologically aberrant, display a dysregulated transcriptome, non-replicating, yet remain viable. Chlamydia lacks the genes necessary to deploy a stringent response, and has very few identified regulatory elements. How it responds to stress is an intriguing question. We hypothesize that during trp limitation the decreased translation of key Chlamydia genes with tandem trp codons triggers a persistent phenotype. The first project goal is to determine how trp limitation impacts the transcriptional regulation by the iron-dependent YtgR repressor. We will use a combination of next-gen RNA sequencing, including ChIP-seq, and targeted transcriptional assays to address this. The second project goal is to determine the mechanism of chlamydial cell division blockage during persistence by focusing on several cell division genes containing tandem trp codons. A combination of genetic approaches and morphological studies will be used to determine this. The third project goal is to monitor host-pathogen interactions, including nutrient acquisition, via cell biological studies. Because several genes associated with host-pathogen interactions contain tandem trp codons, how the inclusion interacts with host pathways and organelles is predicted to be altered by trp starvation; pathways involved in inclusion integrity are maintained whereas those that support chlamydial progression through the developmental cycle are negatively impacted. The proposal aims to mechanistically link trp starvation, regulation of translation by tandem trp codon motifs, and physiological abnormalities linked to persistence. Results will lead to the identification of novel diagnostic and therapeutic targets that may identify and treat asymptomatic chlamydial infections.

项目摘要：串联色氨酸密码子在衣原体持久性中的调节作用衣原体是一种专性细胞内细菌病原体，可引起一系列严重疾病人类。它是细菌性性传播感染 (STI) 的主要原因，也是导致传染性可预防性失明、沙眼的病原体。衣原体感染的主要问题是他们往往无症状且未确诊，这可能导致慢性后遗症，例如盆腔炎炎症性疾病和输卵管因素不孕。因此，衣原体疾病仍然是一个重要的疾病世界各地医疗保健系统的负担。在适应专性细胞内生长时，衣原体显着减小了其基因组大小，并消除了各种途径中的基因，因为它依赖宿主细胞的代谢需求。大多数细菌对氨基酸限制的反应是进行严格的反应，这是一种用于适应营养不良的转录程序状况。严格的反应也与诱导持久细胞直接相关。各种类型的细菌，其代谢活性有限且抗菌素耐药性增加。当色氨酸 (trp) 等营养物质受到限制时，衣原体可能会持续存在。他们是形态异常，转录组失调，不可复制，但仍保持活力。衣原体缺乏部署严格反应所需的基因，并且已鉴定的基因很少监管要素。它如何应对压力是一个有趣的问题。我们假设在 trp 期间限制关键衣原体基因与串联色氨酸密码子的翻译减少触发持久的表型。第一个项目目标是确定色氨酸限制如何影响转录铁依赖性 YtgR 阻遏物的调节。我们将使用下一代 RNA 的组合测序（包括 ChIP-seq）和靶向转录测定可以解决这个问题。第二个项目目标是确定衣原体细胞分裂在持续过程中受阻的机制重点关注几个含有串联色氨酸密码子的细胞分裂基因。基因的组合将使用方法和形态学研究来确定这一点。第三个项目目标是通过细胞生物学研究监测宿主与病原体的相互作用，包括营养获取。因为一些与宿主-病原体相互作用相关的基因含有串联色氨酸密码子，包涵体与宿主途径和细胞器相互作用，预计会因色氨酸饥饿而改变；维持包含完整性的途径，而支持衣原体的途径发育周期的进展受到负面影响。该提案旨在机械地连接色氨酸饥饿、串联色氨酸密码子基序的翻译调节，以及与持久性相关的生理异常。结果将导致新颖的鉴定可以识别和治疗无症状衣原体感染的诊断和治疗目标。