Pathogenesis of Persistent Chlamydial STDs

持续性衣原体性传播疾病的发病机制

基本信息

批准号：
7151468
负责人：
DEBORAH Anne DEAN
金额：
$ 23.6万
依托单位：
CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-15 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7151468
关键词：
Adolescent Adopted Amino Acid Sequence Homology Anabolism Antigenic Variation Baltimore Biology California Cervical Chaperonin 60 Chlamydia Chlamydia trachomatis Chlamydiaceae Chlamydophila pneumoniae Chlamydophila psittaci Cities Clinical DNA DNA Databases DNA Microarray Chip DNA Microarray format Data Development Dioxygenases Disease Dot Immunoblotting Ectopic Pregnancy Enzymes Epidemiologic Studies Epidemiology Evolution Face Family Gene Proteins Genes Genetic Genetic Databases Genetic Polymorphism Genome Genotype Grant Human Resources In Vitro Infection Infertility Inflammation Institutes Instruction Interferon Type II Interferons Intervention Investigation Knowledge Last Name Lead Link Lipopolysaccharides Location Maryland Membrane Proteins Messenger RNA Molecular Profiling Mouse Strains Names Nucleotides Numbers Open Reading Frames Operon Organism Outcome Pathogenesis Pathology Patients Pattern Pediatric Hospitals Pelvic Inflammatory Disease Phenotype Play Postdoctoral Fellow Principal Investigator Printing Proteins Publishing Reading Recombinant Proteins Recurrence Research Research Institute Research Personnel Research Project Grants Research Proposals Reverse Transcriptase Polymerase Chain Reaction Risk Role Sampling Screening procedure Serological Serotyping Serum Sexually Transmitted Diseases Site Students Taxonomy Time Tryptophan Tryptophan Synthase United States Universities Variant Virginia Virulence Woman base cost genetic evolution genetic profiling genome sequencing immunogenic in vivo indoleamine insertion/deletion mutation interest major outer membrane protein member microbial polyclonal antibody programs protein expression prototype rRNA Genes tool young adult

项目摘要

Chlamydia trachomatis(CT) is the leading cause of sexually transmitted diseases (STD) in the developed world. CT infections and their sequelae of pelvic inflammatory disease, ectopic pregnancy, and infertility are responsible for ~80% of the estimated $2.5 billion annual cost of these infections in the United States. Further, up to 50% of women become reinfected and are at increased risk for these sequelae. Many reinfections reflect persistence which likely plays an important role in pathogenesis. The major outer membrane protein is considered to be the immunodominant protein of CT. However, the discovery of open reading frames predicted to encode a nine-member polymorphic membrane protein (Prop) gene (pmp) family in the recently published genome sequence of CT serovar D suggest that these Props may also be important in clalamydial biology. Further, CT contains a partial tryptophan biosynthesis operon (trpR, trpA, trpB) not found in a CT mouse strain (MoPn) or other species of Chlamydia. Tryptophan is essential for chlamydial replication, and tryptophan depletion in vitro results in cblamydial persistence. Our hypothesis is that the prop and tryptophan genes may undergo selection that results in differential expression or activity of these proteins that: 1) consequently determine active or persistent infection; and 2) are significantly involved in pathogenesis as an outcome of persistence or outcome of other factors. By analyzing the genetic profile of prototype and serial recurrent and persistent CT STD patient strains and by correlating these data with epidemiologic and clinical findings, we hope to identify the genes, genetic/protein variation and evolution of this variation in the organism, and how these are linked to persistence and patbogenesis. Thus, this grant will answer broad questions about the genetic and protein basis for persistence and for pathogenesis, and provide important research tools including a Database and DNA microarray that will be of long term benefit to investigators in the field of Chlamydia. The Specific Aims for this grant are to: 1) Sequence the nine pmps, and trpR, trpA, and trpB genes for the 19 prototype serovars of CT and create a DNA microarray for these genes and ompA to differentiate strains of CT, and for use in Aim 2; and 2) Identify polymorphisms in and protein expression of the nine props, specific tryptophan operon genes, and other constitutively expressed genes among serial cervical samples from patients with persistent versus non-persistent CT STDs; correlate the genetic and protein expression profiles of these serial samples with epidemiologic and clinical findings.

沙眼衣原体（CT）是发达国家性传播疾病（STD）的主要原因世界。 CT感染及其引起的盆腔炎、宫外孕、不孕症等后遗症在美国，这些感染每年造成的损失估计为 25 亿美元，其中约 80% 是由病毒造成的。更远，高达 50% 的女性会再次感染，并且出现这些后遗症的风险增加。许多再感染反映出持续性可能在发病机制中发挥重要作用。主要的外膜蛋白是被认为是CT的免疫显性蛋白。然而，开放阅读框的发现预测编码最近发表的九成员多态性膜蛋白（Prop）基因（pmp）家族 CT 血清型 D 的基因组序列表明这些 Props 在衣原体生物学中也可能很重要。此外，CT 还含有 CT 小鼠品系中未发现的部分色氨酸生物合成操纵子（trpR、trpA、trpB） (MoPn) 或其他种类的衣原体。色氨酸对于衣原体复制至关重要，色氨酸体外耗竭导致衣原体持续存在。我们的假设是 prop 和色氨酸基因可能经历导致这些蛋白质差异表达或活性的选择：1) 因此确定活动性或持续性感染； 2）作为以下结果，显着参与发病机制其他因素的持续性或结果。通过分析原型和系列复发和通过将这些数据与流行病学和临床发现相关联，我们希望能够对持续性 CT STD 患者菌株进行分析识别生物体中的基因、遗传/蛋白质变异和这种变异的进化，以及它们是如何发生的与持久性和发病机制有关。因此，这笔赠款将回答有关遗传和持久性和发病机制的蛋白质基础，并提供重要的研究工具，包括数据库 DNA 微阵列将为衣原体领域的研究人员带来长期利益。此项资助的具体目标是： 1) 对 9 个 pmps 以及 trpR、trpA 和 trpB 基因进行测序 19 个 CT 原型血清型，并为这些基因和 ompA 创建 DNA 微阵列，以区分菌株 CT，用于目标 2； 2) 鉴定九种道具的多态性和蛋白质表达，具体患者连续宫颈样本中的色氨酸操纵子基因和其他组成型表达基因患有持续性与非持续性 CT STD；将这些基因和蛋白质表达谱关联起来具有流行病学和临床结果的系列样本。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Predicting phenotype and emerging strains among Chlamydia trachomatis infections.

DOI：
10.3201/eid1509.090272
发表时间：
2009-09
期刊：
Emerging infectious diseases
影响因子：
11.8
作者：
Dean D;Bruno WJ;Wan R;Gomes JP;Devignot S;Mehari T;de Vries HJ;Morré SA;Myers G;Read TD;Spratt BG
通讯作者：
Spratt BG

Association of carotid plaque Lp-PLA(2) with macrophages and Chlamydia pneumoniae infection among patients at risk for stroke.