The Immune Pathogenesis of Prenatal Listeria monocytogenes Infection

抽象的。怀孕是一个错综复杂的过程，对发育中的胎儿表达的异体抗原的扩大耐受性和宿主对感染的防御都是同时维持的。 反过来，当宿主对胎儿的防御或耐受性被破坏时，灾难性的并发症就会出现。许多人类病原体，包括李斯特氏菌、疟原虫、大肠杆菌、B组链球菌、沙门氏菌、衣原体和巨细胞病毒，都有明确的产前感染易感性，通常会导致自然流产或死产。因此，破解自然导致这些疾病的免疫缺陷 妊娠期间宿主防御出现漏洞直接影响到旨在提高对产前感染的免疫力的新疗法。我们已经组装了一套新的转基因小鼠工具，可以重述母体和胎儿抗原之间的自然异质性，并在怀孕期间精确识别具有胎儿特异性的母体免疫细胞。我们的总体假设是，维持对发育中胎儿的耐受性所需的免疫抑制性母体调节T细胞(Tregs)的生理扩张损害了宿主对导致产前感染的病原体的防御。 这是基于我们最近发表的初步研究，确定产前感染李斯特菌的易感性是由扩大的母体Tregs决定的。因此，随着新发现的调节性T细胞之间的异质性和功能专门化，使用独特的细胞内在分子来介导上下文特异性免疫抑制，我们的首要目标是识别母体Treg内在分子，破坏宿主防御，并将这些分子与妊娠期间维持胎儿耐受所需的其他细胞内在分子分离。另一方面，对感染的免疫反应也建立在超越Treg抑制的影响的方式上，Treg抑制刺激免疫激活和最佳宿主防御感染。然而，在怀孕期间，母体Treg抑制的这些短暂减少也对发育中的胎儿产生骨折耐受，这可能导致胎儿损伤或吸收。因此，我们的次要目标是调查 产前感染影响母体Treg介导的胎儿耐受性。前两个目标将建立在我们最近的出版物和使用产前李斯特菌感染的初步研究中所阐述的富有成效的调查路线的基础上，以剖析母体Treg如何导致感染易感性的分子基础，并确定推翻母体Treg抑制所需的李斯特菌特异性毒力决定因素。要建立 为了扩大这些发现的适用性，最终目的将调查是否其他导致产前感染的病原体(如疟原虫、大肠杆菌、B组链球菌、沙门氏菌、衣原体和巨细胞病毒)也会发生压倒母体Treg介导的胎儿耐受。这些实验的完成将揭开母体Tregs如何导致产前感染的易感性，并确定感染诱导的变化 在Treg介导的胎儿耐受中，胎儿在产前感染期间会对发育中的胎儿造成伤害。

Abstract. Pregnancy is an intricately orchestrated process where expanded tolerance to ¿non-self¿ antigens expressed by the developing fetus and host defense against infection are each simultaneously maintained. Reciprocally, catastrophic complications arise when either host defense or tolerance to the fetus is disrupted. A number of human pathogens that includes Listeria, Plasmodium, E. coli, Group B Streptococcus, Salmonella, Chlamydia and cytomegalovirus each have a defined predisposition for prenatal infection that often results in spontaneous abortion or stillbirth. Therefore, unraveling the immune defects that cause these naturally occurring ¿holes¿ in host defense during pregnancy has direct implications for new therapies aimed at boosting immunity against prenatal infection. We have assembled a novel set of transgenic mouse tools that allow the natural heterogeneity between maternal and fetal antigen to be recapitulated, and the precise identification of maternal immune cells with fetal specificity each during pregnancy. Our overall hypothesis is that the physiological expansion of immune suppressive maternal regulatory T cells (Tregs) required for sustaining tolerance to the developing fetus compromises host defense against pathogens that cause prenatal infection. This is based on our recently published initial studies establishing susceptibility to prenatal Listeria infection is dictated by expanded maternal Tregs. Therefore, with the newfound heterogeneity and functional specialization among regulatory T cells that use unique cell-intrinsic molecules to mediate context specific immune suppression, our first goals are to identify the maternal Treg intrinsic molecules that compromise host defense and dissociate these from other cell intrinsic molecules required for sustaining fetal tolerance during pregnancy. On the other hand, the immune response to infection also has built in ways to override the impacts of Treg suppression that stimulate immune activation and optimal host defense against infection. During pregnancy however, these transient reductions in maternal Treg suppression also fracture tolerance to the developing that can dictate fetal injury or resorption. Accordingly, our secondary goals are to investigate how prenatal infection impacts maternal Treg-mediated fetal tolerance. The first two aims will build upon a productive line of investigation illustrated in our recent publications and initial studies using prenatal Listeria infection to dissect the molecular basis for how maternal Tregs cause infection susceptibility, and to identify the Listeria-specific virulence determinants required for overriding maternal Treg suppression. To establish the broader applicability of these findings, the final aim will investigate if overriding maternal Treg-mediated fetal tolerance also occurs for other pathogens that cause prenatal infection (e.g. Plasmodium, E. coli, Group B Streptococcus, Salmonella, Chlamydia, and cytomegalovirus). The completion of these experiments will unravel how maternal Tregs cause prenatal infection susceptibility, and establish how infection-induced shifts in Treg-mediated fetal tolerance dictates injury to the developing fetus during prenatal infection.