Inflammatory Pathways and Prevention Therapies in Placental Infection by Fusobacterium nucleatum

Intrauterine infection with the oral commensal anaerobe Fusobacterium nucleatum has been associated with adverse pregnancy outcomes. We have previously established a mouse model to study the mechanism of hematogenous F. nucleatum leading to fetal and neonatal death. Here, we report that Toll-like Receptor 4 (TLR4) from the maternal rather than paternal, and endothelial rather than hematopoietic cells mediate placental inflammation, especially the production of the proinflammatory cytokine interleukin-1 beta. Downstream of TLR4, a spatiotemporal pattern of the transcription factor NF-kB activation was observed spreading from the decidual endothelium to the surrounding spongiotrophoblasts within the first six hours of infection. Maternal TRIF, an adaptor protein downstream of TLR4 pathway, but not NLRP3, a cytosolic signaling receptor that constitutes inflammasome complex, mediated the fetal and neonatal death. In an effort to find a prophylactic preventive method against the detrimental birth outcome induced by F. nucleatum placental infection, omega-3 fatty acids were tested for their anti-inflammatory properties. Omega-3 oil supplementation in pregnant mice inhibited the transcription and release of inflammatory cytokines, prevented fetal and neonatal death, and also suppressed the proliferation of F. nucleatum in the placenta. Moreover, omega-3 supplementation was shown to enhance neutrophil recruitment to the site of infection. However, omega-3 supplementation did not protect the pregnancy from Listeria monocytogenes infection in vivo, despite the in vitro results where inflammation induced by both Gram-negative and Gram-positive bacteria were suppressed by omega-3 fatty acids. This study presents the first direct evidence of maternal, rather than fetal, signal leading to adverse pregnancy outcome, and suggests an exciting therapeutic potential of dietary omega-3 fatty acids.