New Project 2 Publication Gives Insight to Relationship between GBS, Oxidative Stress Pathways, and Reactive Oxygen Species

Group B Streptococcus, or Streptococcus agalactiae (GBS), is a species of bacterium that has been identified as a significant bacterial cause of adverse birth outcomes, including neonatal morbidity and mortality. During pregnancy, GBS infections can cause ascending infections in the reproductive tract and fetal membranes, which lead to adverse birth outcomes. Unfortunately, the exact mechanisms that allow GBS to evade immune defenses and infect gestational tissues are not entirely understood.

In a new paper in the American Journal of Reproductive Immunology, PROTECT Project 2 researchers describe their work using transcriptomic data and ex vivo experiments to better understand these mechanisms. The team began their study by reanalyzing a transcriptomic dataset from a previous study where they inoculated fetal membrane explants with GBS, specifically assessing the impact of GBS on oxidative stress pathways and genes involved in the responses to reactive oxygen species (ROS). Through their analysis, researchers saw that 31 genes associated with oxidative stress were significantly changed in the membrane explants with GBS. They also saw that pathways involved in oxidative stress and ROS responses were activated after encountering GBS.

After analyzing the impact of GBS on oxidative stress and ROS pathways, researchers conducted additional experiments to test their hypothesis that antioxidant treatment could be used to reduce inflammatory responses in fetal membranes that are induced by pathogens, such as GBS. To do so, researchers treated the GBS-inoculated membrane explants with the antioxidant N-acetylcysteine (NAC). They saw that the NAC treatment suppressed the release of GBS-induced pro-inflammatory cytokines in fetal membrane tissues. These observations indicate that ROS are involved in the regulation of GBS-induced immune responses. Researchers further investigated how ROS contribute to regulating inflammation using explants treated with lipoteichoic (LTA) and lipopolysaccharide (LPS), which are bacteria-associated toxins that cause inflammation. After treating some of these explants with NAC and some without it, researchers observed that NAC treatment decreased the LPS- and LTA-stimulated pro-inflammatory cytokine release in fetal membrane tissue.

The findings from these experiments give insight into the molecular mechanisms that regulate immune defenses against GBS infection in fetal membranes. ROS metabolism and oxidative stress genes in fetal membranes were shown to be upregulated when treated with GBS. Then, co-treatment of these membranes with the antioxidant NAC were shown to suppress pro-inflammatory cytokine expression.

Inflammation plays a nuanced role in the body. While overactivation of inflammation leads to adverse health effects, some controlled levels of inflammation are necessary for mounting effective immune responses to pathogenic organisms like infectious bacteria. Project 2’s findings suggest that redox signaling is a critical component for activating immune responses to pathogenic bacteria in the fetal membranes and that while antioxidants may suppress harmful inflammation pathways, they may also inhibit immune responses that are necessary to fight off intrauterine infections. Furthermore, exposure to some environmental toxicants, including those found at Superfund sites like trichloroethylene and phthalates, can cause upregulation of antioxidant defense systems, potentially interfering with antimicrobial defense pathways. Therefore, further studies need to be conducted to understand precisely how environmental exposures and intrauterine pathogens interact to affect pregnancy health and the role that antioxidants could play in mitigating these effects.

These experiments and analyses contribute to a clearer understanding of how ROS govern the innate immune response to GBS infection and other pathogen-induced inflammation. These insights can help contribute to the future development of strategies for mitigating adverse pregnancy outcomes that arise from GBS infection, environmental toxicant exposures, or the combined effects of both.

For all details on the research methods, findings, and conclusions, you can access the full paper here.