Cytosolic DNA Sensor In Trophoblast Cells Protects Against Listeria Monocytogenes Infection During Pregnancy

Placental infections compromise the health of both mother and offspring. Besides uncalculated economic loss of livestock, they represent a major source of human morbidity and mortality. There is accumulating epidemiological and experimental evidence that maternal infection is a significant risk factor for adverse pregnancy outcomes. Pregnancy leads to a generalized suppression of the adaptive immune system. And this immunosuppressed state prevents maternal rejection of the fetus but has the unfortunate consequence of increasing maternal susceptibility to certain infectious agents. Therefore, effective anti-intrauterin infection mechanisms are important in maintaining a viable pregnancy.The placenta is a dynamic organ consisting of maternal and fetal tissues, forming an impermeable physical and biological barrier that protects the fetus against pathogens while also providing an environment of immunological tolerance for the fetal allograft. How the placenta accomplishes these contradictory tasks is unknown. Nevertheless, accumulated evidences suggest that the placenta has effective innate defenses against microbial invasion and replication. Recent studies suggest that the placenta functions as an active immunologic barrier by the trophoblast recognizing and responding to microbes through PRRs. Thus, the placenta has the ability to control microorganisms that may injure the embryo/fetus, thereby protecting the pregnancy. However, the role of AIM2 and IFI16 in orchestrating immune responses to dsDNA or in regulating immune responses to intrauterine infection at the maternofetal interface has not been examined further. Our results indicate that trophoblasts express functional AIM2, DHX9/36, LRRFIP1, KU70 and ZBP1 mRNA. IFI16 is mainly localized in the nucleus, and AIM2 is localized in the cytoplasm. The results demonstrated that first-trimester trophoblast cells express functional AIM2 and IFI16 and generate differential cytokines and chemokines profiles in response to dsDNA. The induction of IL-8, IL-6 and CXCL10 secretion via AIM2 activation is dependent on the IκB, p38 and JNK signaling pathways; MCP-1 secretion is dependent on the p38 and JNK signaling pathways; IL-1β secretion is dependent on AIM2 inflammasome. The induction of IFN-β and CXCL10 via IFI16 is dependent on the IRF3 signaling pathways.L. monocytogenes is a ubiquitous, facultative intracellular, Gram-positive bacterial pathogen that can cross the intestinal, placental and blood-brain barriers, leading to gastroenteritis, maternofetal infections, and meningoencephalitis, respectively. L. monocytogenes causes life-threatening disease, particularly in immunocompromised individuals, pregnant women, and neonates. The rate of infection is highest among neonates, adults>60 years of age, immunocompromised patients and pregnant women. Pregnant women account for 27% of all cases. Moreover, pregnant women have a 20-fold increased risk of developing diseases as compared with the general population. During pregnancy L. monocytogenes has a predilection for replication at the maternofetal interface in the decidua basalis and the placenta, resulting in abortion, stillbirth, preterm labor, fetal malformation and neonatal mortality and morbidity. However, the molecular mechanisms of the placental defenses against L. monocytogenes are still not completely understood.Here, we use mouse models and cell culture systems to characterize the role of AIM2 during L. monocytogenes infection. Macroscopic analysis of the mothers and the uterine horns harvested on ED 13.5 from C57BL/6J and AIM2-deficient mice revealed a striking difference in vaginal bleeding, uterine and fetal size, and indicative of a high fetal loss rate in AIM2-deficient mice. More significantly, the AIM2"’ labyrinthine layer was severely disrupted, and pro-inflammatory cytokines were significantly increased in both the placenta and fetus. Upon L. monocytogenes infection or dsDNA transfection, the production of IL-1β and IL-6 in first-trimester trophoblast cells enhanced resistance to L. monocytogenes intracellular growth; the production of IL-8 and MCP-1 recruit polymorphonuclear leukocytes and monocytes to the maternofetal interface in response to L. monocytogenes infection. Taken together, these results suggest a new function of AIM2 in trophoblasts that allows effective defense mechanisms against L. monocytogenes intracellular growth and represents a significant bottleneck in the vertical transmission of this pathogen.