Lack of Inflammatory Response in Mouse Embryonic Cells to Listeria Infection

Approximately 1 in 5 pregnancies in the United States results in miscarriage, with a significant percentage of these losses attributed to failed implantation due to immunological challenges encountered by the early embryo. Recent research has shown that key cell types within mouse blastocysts, including embryonic stem cells (ESCs) and trophoblast stem cells (TSCs), exhibit remarkable resilience against the cytotoxic effects associated with viral infections and embryotoxic cytokines, such as TNFα and IFNγ, both of which are known to hinder blastocyst development. However, the immune properties of the preimplantation stage embryo, specifically the blastocyst, remain poorly understood. Using mouse cell model, this study aims to investigate how embryos at the blastocyst stage respond to bacterial pathogens. Listeria monocytogenes (Lm), a gram-positive intracellular bacterium known to cause severe pregnancy complications, including miscarriages in humans, serves as an appropriate model for this study. I hypothesize that the attenuated innate immunity of ESCs and TSCs allows these cells to evade the cytotoxic effects of Lm infection, serving as a self-protective mechanism that limits bacterial entry during early embryogenesis. To test this hypothesis, comparative experiments were conducted using mouse embryonic fibroblasts (MEFs) and a fibroblast-like cell line (10T1/2) as controls. The results from this study showed that upon Lm infection, ESCs and TSCs exhibit an attenuated expression of pro-inflammatory cytokines, an inactivated NF-κB signaling pathway, and low infectivity, unlike the responses observed in MEFs and 10T1/2 cells. Furthermore, similar attenuated immune responses were observed when ESCs and TSCs were exposed to Lm-conditioned medium derived from infected macrophages, which contained various inflammatory cytokines. In conclusion, the results from this thesis presents evidence that the attenuated innate immunity observed in ESCs and TSCs is likely an intrinsic feature that may offer a developmental advantage during early embryogenesis.