Immune responses to infection at the maternal-fetal interface

描述（由申请人提供）：妊娠是一种独特的免疫学情况，因为胎儿与母亲的基因不相同。胎盘在保护胎儿免受母体免疫系统的攻击方面起着重要作用，同时保护胎儿免受病原体的侵害。胎盘免疫系统如何完成这些看似矛盾的任务的细节在很大程度上是未知的。概述/假设：我们假设胎盘的母体免疫细胞，特别是位于蜕膜（妊娠子宫内膜）中的巨噬细胞，以独特的方式保护该器官免受病原体的侵害。具体目标：（1）确定蜕膜巨噬细胞对感染的反应;（2）研究干扰素β和干扰素诱导的四肽重复序列蛋白（IFIT）在胎盘宿主防御中的作用。方法：我们将研究胎盘对兼性胞内细菌病原体单核细胞增生李斯特菌（LM）的天然免疫应答。人类和其他哺乳动物妊娠期间感染LM可导致妊娠并发症，如早产。除了临床相关性外，LM还非常适合实验分析。我们将在体外利用原代人类和小鼠胎盘巨噬细胞和胎盘组织的组合来研究这些细胞如何对LM做出反应，并评估它们的反应与其他组织特异性巨噬细胞的反应有何不同（目的1）。为了在体内证实我们的发现，我们将采用妊娠小鼠模型。除了野生型小鼠，我们建议使用具有特定遗传背景的小鼠，以剖析细胞因子信号通路（例如IFN γ）在防御胎盘感染中的作用（目的2）。培训目标：该F32培训奖的另一个主要目标是Gabrielle Rizzuto博士在微生物发病机制和胎盘生物学方面的严格博士后研究培训，并协调使用人类和小鼠研究工具。预期结果：我们预测这个项目的结果将是（1）更清楚地了解母体免疫系统如何与胎盘中的病原体相互作用;（2）受训者将处于开始的有利位置 作为一名医生兼科学家的成功的独立职业生涯。相关性：全球新生儿死亡的主要原因是早产，胎盘感染是早产最常见的原因。我们将开始用一种独特的方法来解决这个问题，这种方法使用原代人类胎盘组织和一种重要的人类细菌病原体，结合妊娠小鼠，一种遗传学上易于处理的模型来证实和扩大我们发现的体内相关性。

DESCRIPTION (provided by applicant): Pregnancy is a unique immunological situation because the fetus is not genetically identical to the mother. The placenta plays an important role in protecting the fetus from attack by the maternal immune system while at the same time protects the fetus from pathogens. The details of how the placental immune system accomplishes these seemingly contradictory tasks are largely unknown. Overview/Hypothesis: We hypothesize that the maternal immune cells of the placenta, specifically the macrophages located in the decidua (lining of the pregnant uterus), defend this organ against pathogens in a unique manner. Specific Aims: (1) To determine the decidual macrophage response to infection; (2) To investigate the role of IFN� and interferon-inducible proteins with tetracopeptide repeats (IFITs) in placental host defense. Methods: We will study the placental innate immune responses to the facultative intracellular bacterial pathogen Listeria monocytogenes (LM). LM infection during pregnancy in humans and other mammals leads to pregnancy complications such as preterm labor. In addition to its clinical relevance, LM is highly amenable to experimental analysis. We will utilize a combination of primary human and mouse placental macrophages and placental tissue in vitro to investigate how these cells respond to LM, and evaluate how their response differs from that of other tissue-specific macrophages (Aim 1). To confirm our findings in vivo, we will employ a pregnant mouse model. In addition to wild type mice, we propose to use mice with specific genetic backgrounds in order to dissect the role of cytokine signaling pathways (e.g. IFN�) in the defense against placental infection (Aim 2). Training Goal: The other major goal for this F32 training award is the rigorous post-doctoral research training of Dr. Gabrielle Rizzuto in microbial pathogenesis and placental biology with the concerted use of human and murine research tools. Expected Results: We predict the results of this project will be (1) a clearer understanding of how the maternal immune system interacts with pathogens in the placenta; and (2) that the trainee will be well-positioned to begin a successful independent career as a physician-scientist. Relevance: The leading cause of newborn death worldwide is pre-term birth, and infection of the placenta is the most common cause of pre-term birth. We will begin to tackle this problem with a unique approach using primary human placental tissues and an important human bacterial pathogen, in conjunction with the pregnant mouse, a genetically tractable model to confirm and expand the in vivo relevance of our findings.