Effect of polymicrobial infection on trophoblast-macrophage interactions

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Pregnant women are more likely to experience severe complications, mortality and preterm birth, associated with viral infections compared with the general population. The presence of the placenta and the immunological adaptation of women to the fetus alter the immunologic response of the mother to microorganisms, although the reasons behind the increased susceptibility are poorly understood. The generalization of pregnancy as a condition of immune suppression is misleading and prevents the determination of adequate guidelines for treating pregnant women during pandemics. Therefore, it is important to better understand the unique immunologic conditions of pregnant women and how this population responds to viral and bacterial infections. The trophoblast, just like an innate immune cell, can recognize the presence of bacteria, viruses, and other microbes as well as dying cells and damaged tissue. Upon recognition, the trophoblast will often secrete a specific set of cytokines that in turn, will act upon the immune cells within the decidua (macrophages, Tregs, NK cells), "educating" them to work together in support of the growing fetus/placenta, or to defend against microbial invasion. Interestingly, trophoblast cells, as well as decidual macrophages display low sensitivity to bacterial products normally present, therefore preventing inflammatory response that could jeopardize the success of the pregnancy. Our central hypothesis is that viral infection of the placenta sensitizes the mother to bacterial products triggering an inflammatory response that induces pretenm birth and maternal mortality. The trophoblast, through the production of type I Interferons (IFN) is able to regulate maternal immune functions; to control a viral infection and prevent the transfer of virus to the fetus. However, following infection, the virus induces complex intracellular events that affect many components of host signaling pathways. Specifically we demonstrate that virus by inhibiting IFNBeta, is able to enhance Toll-like receptor 4 (TLR4) induced NF-kappaB activity, promoting an inflammatory response. We will elucidate: 1) the mechanism by which viral infection modulates the TLR4-NF-kappaB pathway in the trophoblast; 2) the effect of trophoblast viral infection on macrophage differentiation and function; and 3) the role of placenta-derived type I interferons on the maternal response to viral infection. Our specific aims are as follows: Aim 1. To determine the role of the type I interferon-TAM receptor pathway and Twist in the regulation of NF-kappaB in trophoblast cells. Aim 2. To Determine the mechanism by which virus changes trophoblast-macrophage crosstalk. Aim 3: Characterize the role of placental interferon in mortality and preterm birth using a murine model. Upon completion of these aims we will have a better understanding of how infection-associated preterm birth is the result of a polymicrobial infection and typically not due to infection by a single microorganism.