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The molecular basis for integration of the Chlamydial responses to iron and tryptophan limitation

衣原体对铁和色氨酸限制反应整合的分子基础

基本信息

批准号：
9766069
负责人：
Nicholas David Pokorzynski
金额：
$ 3.77万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9766069
关键词：
Acute Adopted Anabolism Biological Assay Biology Cells ChIP-seq Chlamydia Chlamydia Infections Chlamydia trachomatis Chronic Chronic Disease Clinical Clinical Treatment Code Codon Nucleotides DNA DNA Binding Data Development Elements Etiology Event Evolution Frequencies Genes Genetic Genetic Transcription Genomics Goals Growth Homeostasis Human Immune Immunologics In Vitro Infection Interferon Type II Internet Iron Knowledge Link Maintenance Mediating Methods Modeling Molecular Molecular Genetics Morphology N-terminal Nutrient Nutritional Operon Organism Pathogenesis Pathology Pathway interactions Patients Pelvic Inflammatory Disease Pharmacology Phenotype Play Process Promoter Regions Regulation Regulatory Element Regulon Reporting Repression Research Role Sexually Transmitted Diseases Starvation Stimulus Stress Techniques Transcription Repressor/Corepressor Translating Translations Tryptophan Vaccines Woman biological adaptation to stress clinical Diagnosis deprivation design in vitro Assay innovation insight novel pathogen permease promoter reproductive tract response stressor therapeutic development transcriptome sequencing tubal infertility

项目摘要

7. Project Summary/Abstract Infections of the human genital tract by the obligate intracellular pathogen Chlamydia trachomatis are among the most highly reported sexually transmitted infections both in the U.S. and abroad. Asymptomatic chlamydial infections are highly prevalent and contribute to the frequency of undiagnosed and untreated patients. Untreated chlamydial infections can promote the development of serious sequelae in women, including pelvic inflammatory disease and tubal factor infertility. Despite these severe consequences, how Chlamydia manifest asymptomatically remains poorly understood. A growing body of evidence implicates an aberrant chlamydial growth phenotype, known as persistence, in abetting these chronic diseases. Varied and seemingly unrelated stimuli are known to facilitate persistence in vitro, yet it is unclear whether these various insults arrive at persistence through convergent or divergent pathways. Limiting the availability of iron to Chlamydia promotes persistence, but little is understood about how chlamydial species respond to iron limitation. The only identified iron-dependent transcriptional regulator in Chlamydia is represented by YtgR, the activity of which requires cleavage from an N-terminal permease domain, YtgC. Briefly limiting iron to C. trachomatis significantly induces the expression of the sole tryptophan (Trp) biosynthetic genes trpBA, indicating a previously undescribed iron- dependent mode of regulation controls Trp biosynthesis in C. trachomatis. YtgC possesses a unique codon motif of three sequential Trp residues (WWW), necessitating Trp availability for the translation of YtgC and thus YtgR. Intriguingly, starvation of Trp is one of the principal methods of inducing persistence as it represents a critical nutrient for Chlamydia. It is therefore possible that the loss of YtgR due to chronic Trp starvation would result in the dysregulation of the YtgR regulon, contributing to the induction of persistence. To investigate this hypothesis, we propose to utilize recent advances in chlamydial genetics to elucidate both the iron-dependent and Trp- dependent regulons of YtgR. First, we will define the iron-dependent YtgR regulon to understand the contribution of this regulator to the development of persistence induced via iron limitation. Secondly, we will elucidate the molecular mechanisms underpinning the iron-dependent regulation of trpBA. Finally, we will assess the role of the WWW motif in maintaining the YtgR regulon as a function of Trp availability. Successful completion of this research will provide the first mechanistic link between two separate stimulators of persistence, potentially offering key insights into the molecular basis for asymptomatic and chronic chlamydial infections.

7. 项目总结/文摘