Impact of Lactobacillus effectors across gestation

About This Grant

PROJECT SUMMARY Over 10% of pregnancies around the world end in preterm birth or adverse pregnancy outcomes. Recent clinical profiling studies have shown that vaginal inflammation resulting from loss of vaginal lactobacilli is significantly correlated with adverse pregnancy outcomes from reduced fertility and implantation to preterm birth. Presence of health-associated lactobacillus species is enriched during pregnancy. However, the mechanisms by which these bacteria mediate their protective effects and promote pregnancy remain unclear. We recently identified a family of anti-inflammatory effectors produced by vaginal lactobacilli and depleted in people with bacterial vaginosis. These compounds inhibit both NFκB and interferon signaling downstream of multiple pattern recognition receptors including Toll-like receptor (TLR) 3 and 4. These compounds have been shown to have cell-type specific effects with the broadest range of activity on immune cells. Intravaginal application of these compounds to pregnant mice significantly rescues fetal demise via as yet unknown mechanisms. We hypothesize that vaginal lactobacilli promote fertility and healthy pregnancies by production of these small molecule effectors that suppress inflammatory effects on the host decidua and developing fetus. We will test this hypothesis with two aims. First, we will test if intravaginal application of lactobacilli-produced compounds can rescue decidualization markers in human endometrial stromal cells and in mice under TLR- driven inflammatory contexts (Aim 1). Next, we will test if these compounds suppress inflammatory signaling in placental trophoblasts cell lines. Finally, we will use the TLR-induced fetal demise model to map the immune correlates of intravaginal rescue, examining immune cell populations at the vaginal draining lymph node, the decidua and the placenta. We anticipate being able to identify both cell intrinsic impact of vaginal lactobacilli effectors in relevant human cells but also specific immune signaling mechanisms by which the vaginal mucosa impact maternal and fetal health.