Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, New York, USA.
Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
Am J Reprod Immunol. 2024 Jan;91(1):e13807. doi: 10.1111/aji.13807.
Infection during pregnancy is a significant public health concern due to the increased risk of adverse birth outcomes. Group B Streptococcus or Streptococcus agalactiae (GBS) stands out as a major bacterial cause of neonatal morbidity and mortality. We aimed to explore the involvement of reactive oxygen species (ROS) and oxidative stress pathways in pro-inflammatory responses within human fetal membrane tissue, the target tissue of acute bacterial chorioamnionitis.
We reanalyzed transcriptomic data from fetal membrane explants inoculated with GBS to assess the impact of GBS on oxidative stress and ROS genes/pathways. We conducted pathway enrichment analysis of transcriptomic data using the Database for Annotation, Visualization and Integrated Discovery (DAVID), a web-based functional annotation/pathway enrichment tool. Subsequently, we conducted ex vivo experiments to test the hypothesis that antioxidant treatment could inhibit pathogen-stimulated inflammatory responses in fetal membranes.
Using DAVID analysis, we found significant enrichment of pathways related to oxidative stress or ROS in GBS-inoculated human fetal membranes, for example, "Response to Oxidative Stress" (FDR = 0.02) and "Positive Regulation of Reactive Oxygen Species Metabolic Process" (FDR = 2.6*10 ). There were 31 significantly changed genes associated with these pathways, most of which were upregulated after GBS inoculation. In ex vivo experiments with choriodecidual membrane explants, our study showed that co-treatment with N-acetylcysteine (NAC) effectively suppressed the release of pro-inflammatory cytokines (IL-6, IL-8, TNF-α) and prostaglandin PGE2, compared to GBS-treated explants (p < .05 compared to GBS-treated samples without NAC co-treatment). Furthermore, NAC treatment inhibited the release of cytokines and PGE2 stimulated by lipoteichoic acid (LTA) and lipopolysaccharide (LPS) in whole membrane explants (p < .05 compared to LTA or LPS-treated samples without NAC co-treatment).
Our study sheds light on the potential roles of ROS in governing the innate immune response to GBS infection, offering insights for developing strategies to mitigate GBS-related adverse outcomes.
孕期感染是一个重大的公共卫生问题，因为它会增加不良出生结局的风险。B 群链球菌或无乳链球菌（GBS）是导致新生儿发病率和死亡率的主要细菌性病因。我们旨在探讨活性氧（ROS）和氧化应激途径在急性细菌性绒毛膜羊膜炎的靶组织——人胎膜组织中的促炎反应中的作用。
我们重新分析了用 GBS 接种的胎膜外植体的转录组数据，以评估 GBS 对氧化应激和 ROS 基因/途径的影响。我们使用数据库注释、可视化和综合发现（DAVID），一种基于网络的功能注释/途径富集工具，对转录组数据进行途径富集分析。随后，我们进行了离体实验，以验证抗氧化剂治疗是否可以抑制病原体刺激的胎膜炎症反应的假说。
使用 DAVID 分析，我们发现 GBS 接种的人胎膜中与氧化应激或 ROS 相关的途径明显富集，例如“对氧化应激的反应”（FDR=0.02）和“活性氧物质代谢过程的正调节”（FDR=2.6*10-4）。有 31 个与这些途径相关的基因显著改变，其中大多数在 GBS 接种后上调。在绒毛膜蜕膜外植体的离体实验中，我们的研究表明，与 GBS 处理的外植体相比，用 N-乙酰半胱氨酸（NAC）共同处理可有效抑制促炎细胞因子（IL-6、IL-8、TNF-α）和前列腺素 PGE2 的释放（与未用 NAC 共同处理的 GBS 处理的外植体相比，p<0.05）。此外，NAC 处理抑制了全膜外植体中脂磷壁酸（LTA）和脂多糖（LPS）刺激的细胞因子和 PGE2 的释放（与未用 NAC 共同处理的 LTA 或 LPS 处理的外植体相比，p<0.05）。
我们的研究揭示了 ROS 在调节对 GBS 感染的固有免疫反应中的潜在作用，为制定减轻 GBS 相关不良结局的策略提供了依据。
