Effect of polymicrobial infection on trophoblast-macrophage interactions

与一般人群相比，孕妇更容易出现与病毒感染有关的严重并发症、死亡和早产。胎盘的存在和妇女对胎儿的免疫适应改变了母亲对微生物的免疫反应，尽管增加易感性背后的原因尚不清楚。将怀孕普遍化为免疫抑制的一种情况具有误导性，并妨碍确定在大流行期间治疗孕妇的适当准则。因此，更好地了解孕妇独特的免疫状况以及这一人群对病毒和细菌感染的反应是很重要的。滋养层就像先天免疫细胞一样，可以识别细菌、病毒和其他微生物的存在，也可以识别垂死的细胞和受损的组织。一旦被识别，滋养细胞通常会分泌一组特定的细胞因子，这些细胞因子反过来会作用于蜕膜内的免疫细胞（巨噬细胞、treg细胞、NK细胞），“教育”它们协同工作，以支持生长中的胎儿/胎盘，或防御微生物入侵。有趣的是，滋养细胞和蜕膜巨噬细胞对通常存在的细菌产物表现出较低的敏感性，因此可以防止可能危及妊娠成功的炎症反应。我们的中心假设是，胎盘的病毒感染使母亲对细菌产物敏感，引发炎症反应，导致假分娩和产妇死亡。滋养细胞通过产生I型干扰素（IFN）调节母体免疫功能；控制病毒感染，防止病毒传染给胎儿。然而，在感染后，病毒诱导复杂的细胞内事件，影响宿主信号通路的许多组成部分。具体来说，我们证明了病毒通过抑制IFNBeta，能够增强toll样受体4 （TLR4）诱导的NF-kappaB活性，促进炎症反应。我们将阐明：1)病毒感染调节滋养细胞中TLR4-NF-kappaB通路的机制；2)滋养细胞病毒感染对巨噬细胞分化和功能的影响；3)胎盘源性I型干扰素在母体病毒感染应答中的作用。我们的具体目标如下：

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.