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: 8798573
• 负责人: Seth T Walk
• 金额: $ 18万
• 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/8798573
• 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; Health; 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; 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）是生殖年龄女性中最常见的阴道疾病。 BV增加了女性患有性传播疾病的风险，包括HIV，以及发展不育症和骨盆炎症性疾病。在孕妇中，BV增加了预期出生和第二孕期和第三孕期的风险。此外，患有BV的母亲出生的新生儿的出生体重，高炎症反应，长期发育问题和死亡率的风险较高。鉴于该疾病的临床相关性，在当前对BV发作和进展的不完全理解中弥合差距很重要。几乎总是观察到BV症状与阴道细菌组成的巨大变化一起观察到。另一个普遍观察到的变化是阴道pH值增加（正常<4.5 vs. Bv> 4.5）。这两种观察结果可能是因果关系的，因为低pH值为健康的阴道片中的病原体和其他细菌物种提供了物理障碍，或者在健康的阴道中含量低。作者最近确定并发表了BV之间的三方关联，两种多胺（perrescine和Cadaverine）的水平升高，以及包括拨号板，Prevotella和链球菌在内的几个细菌属。氨基酸脱羧和多胺产生是一种众所周知的细菌抗抗性和缓解机制，我们假设它在BV发育过程中负责增加阴道pH。氨基酸脱羧会消耗细胞内氢离子，形成通过氨基酸/多胺（AAP）特异性抗胞毒剂在细胞外积极泵送的多胺。基于AAP的酸抗性尚未在阴道微生物群中表征。因此，该项目提议通过从元基因组确定阴道区域中独特的氨基酸脱羧途径的丰度和广度来解决上述假设，并确定编码它们的微生物物种；在BV之前，之中和之后，从元转录确定其转录活性；最后，通过隔离重要的阴道菌株并精确表征体外条件 这导致AAP途径利用。