Microbial Polyamine-Mediated Reductions in Vaginal Acidity; A Mechanistic Underst

微生物多胺介导的阴道酸度降低；

• 批准号: 8683865
• 负责人: Seth T Walk
• 金额: $ 21.6万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-05 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8683865
• 关键词: Accounting; Acidity; Acids; Address; Age; Amino Acids; Arginine; Bacteria; Bacterial Vaginosis; Biological Assay; Cadaverine; Carboxy-Lyases; Cells; Data; Decarboxylation; Development; Disease; Escherichia coli; Exhibits; Funding; Genes; HIV; In Vitro; Infertility; Inflammatory; Inflammatory Response; Investigation; Knowledge; Lead; Link; Low Birth Weight Infant; Lysine; Mediating; Mobiluncus; Mothers; Odors; Ornithine; Orthologous Gene; Pathway interactions; Patients; Pelvic Inflammatory Disease; Pelvis; Perinatal mortality demographics; Phase; Phenotype; Polyamines; Pregnant Women; Prevotella; Production; Protons; Publishing; Pump; Putrescine; Resistance; Risk; Sampling; Sexually Transmitted Diseases; Smell Perception; Streptococcus; Symptoms; Taxon; Term Birth; Third Pregnancy Trimester; Vagina; Vaginal Diseases; Variant; Walking; Woman; Work; abortion; antiporter; arginyllysine; base; cell growth; clinically relevant; extracellular; member; microbial; mortality; neonate; novel therapeutics; pathogen; public health relevance; reproductive

DESCRIPTION (provided by applicant): Bacterial vaginosis (BV) is the most common vaginal disorder among reproductive age women. BV increases a woman's risk of acquiring sexually transmitted diseases, including HIV, as well as developing infertility and pelvic inflammatory disease. In pregnant women, BV increases the risk of pre-term birth and second- and third-trimester abortion. Additionally, neonates born to mothers with BV have elevated risks of critically low birth weights, hyper-inflammatory responses, long-term developmental problems, and mortality. Given the clinical relevance of this disease, it is important to bridge gaps in the currently incomplete understanding of BV onset and progression. BV symptoms are almost always observed alongside a dramatic change in the composition of vaginal tract bacteria. Another commonly observed change is an increase in vaginal pH (normal <4.5 vs. BV>4.5). These two observations may be causally related because low pH provides a physical barrier to pathogens and other bacterial species that are either not normally found, or are at low abundances, in the healthy vaginal tract. The authors recently identified and published a tripartite association between BV, increased levels of two polyamines (putrescine and cadaverine), and several bacterial genera, including Dialister, Prevotella, and Streptococcus. Amino-acid decarboxylation and polyamine production is a well-known bacterial acid resistance and mitigation mechanism and we hypothesize it is responsible for increasing vaginal pH during BV development. Amino acid decarboxylation consumes intracellular hydrogen ions to form polyamines that are actively pumped outside the cell via amino acid/polyamine (AAP)-specific antiporters. AAP-based acid resistance has yet to be characterized among the vaginal microbiota. This project therefore proposes to address the above hypothesis by metagenomically determining the abundance and breadth of unique amino-acid decarboxylation pathways in the vaginal tract and identifying the microbial species encoding them; metatranscriptomically determining their transcriptional activity before, during and after BV; and finally by isolating important vaginal strains and precisely characterizing the in vitro conditions that lead to AAP pathway utilization.

描述（由申请人提供）：细菌性阴道病（BV）是育龄妇女中最常见的阴道疾病。BV增加了妇女感染性传播疾病（包括艾滋病毒）以及患不孕症和盆腔炎的风险。在孕妇中，BV会增加早产和中晚期流产的风险。此外，患有BV的母亲所生的新生儿具有极低出生体重、高度炎症反应、长期发育问题和死亡率的升高风险。鉴于这种疾病的临床相关性，重要的是弥合目前对BV发作和进展的不完全理解的差距。BV症状几乎总是伴随着阴道细菌组成的急剧变化而观察到的。另一个常见的变化是阴道pH值升高（正常值<4.5 vs. BV>4.5）。这两个观察结果可能存在因果关系，因为低pH值为健康阴道中通常未发现或丰度较低的病原体和其他细菌物种提供了物理屏障。作者最近确定并发表了BV、两种多胺（腐胺和尸胺）水平升高与几种细菌属（包括小杆菌属、普雷沃菌属和链球菌属）之间的三方关联。氨基酸脱羧和多胺的产生是一种众所周知的细菌耐酸性和缓解机制，我们假设它是BV发展过程中阴道pH值升高的原因。氨基酸脱羧消耗细胞内氢离子以形成多胺，所述多胺通过氨基酸/多胺（AAP）特异性反向转运蛋白被主动泵送到细胞外。基于AAP的耐酸性尚未在阴道微生物群中表征。因此，该项目提出通过以下方法来解决上述假设：宏基因组学确定阴道中独特氨基酸脱羧途径的丰度和宽度，并鉴定编码它们的微生物物种;元转录组学确定它们在BV之前、期间和之后的转录活性;最后通过分离重要的阴道菌株并精确表征体外条件 导致AAP途径的利用。