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

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 会增加女性感染性传播疾病（包括艾滋病毒）以及患不孕症和盆腔炎的风险。对于孕妇来说，细菌性阴道病会增加早产和妊娠中期和晚期流产的风险。此外，患有 BV 的母亲所生的新生儿出生体重极低、过度炎症反应、长期发育问题和死亡的风险较高。鉴于该疾病的临床相关性，弥合目前对 BV 发病和进展的不完全理解的空白非常重要。 BV 症状几乎总是伴随着阴道细菌组成的巨大变化而出现。另一个常见的变化是阴道 pH 值升高（正常 <4.5 与 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不存在或丰度较低的病原体和其他细菌物种提供了物理屏障。作者最近发现并发表了 BV、两种多胺（腐胺和尸胺）水平升高以及几种细菌属（包括 Dialister、普雷沃氏菌属和链球菌属）之间的三重关联。氨基酸脱羧和多胺产生是众所周知的细菌耐酸性和缓解机制，我们假设它是 BV 发育过程中阴道 pH 值升高的原因。氨基酸脱羧消耗细胞内氢离子形成多胺，多胺通过氨基酸/多胺（AAP）特异性反向转运蛋白主动泵出细胞外。阴道微生物群中基于 AAP 的耐酸性尚未得到表征。因此，该项目建议通过宏基因组学确定阴道中独特氨基酸脱羧途径的丰度和广度并鉴定编码它们的微生物物种来解决上述假设；通过宏转录组学测定 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 途径利用。

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.