The Immune Pathogenesis of Prenatal Listeria monocytogenes Infection

抽象的。妊娠是一个错综复杂的过程，在这个过程中，对发育中的胎儿表达的非自身抗原的耐受性增强，宿主对感染的防御能力也同时得到维持。 反过来，当宿主的防御或对胎儿的耐受被破坏时，就会出现灾难性的并发症。许多人类病原体，包括李斯特菌、疟原虫、E.大肠杆菌、B组链球菌、沙门氏菌、衣原体和巨细胞病毒每一种都有明确的产前感染倾向，经常导致自然流产或死产。因此，揭开导致这些自然的免疫缺陷， 在怀孕期间宿主防御中出现的“漏洞”对旨在增强对产前感染的免疫力的新疗法有直接影响。我们已经组装了一套新的转基因小鼠工具，使母体和胎儿抗原之间的天然异质性被概括，并在怀孕期间准确识别母体免疫细胞与胎儿特异性。我们的总体假设是，维持对发育中的胎儿的耐受性所需的免疫抑制性母体调节性T细胞（T细胞）的生理扩增损害了宿主对引起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，建立产前李斯特菌感染的易感性是由扩展的母体THP决定的。因此，随着新发现的异质性和功能的专业化之间的调节性T细胞，使用独特的细胞内在分子介导的背景特异性免疫抑制，我们的首要目标是确定母体Treg内在分子，损害宿主防御和解离这些从其他细胞内在分子所需的维持胎儿耐受在怀孕期间。另一方面，对感染的免疫应答也建立了克服Treg抑制的影响的方法，Treg抑制刺激免疫激活和最佳宿主防御感染。然而，在妊娠期间，这些母体Treg抑制的短暂减少也会破坏对发育的耐受性，这可能决定胎儿损伤或吸收。因此，我们的次要目标是研究如何 产前感染影响母体Treg介导的胎儿耐受。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示的生产线调查的基础上，以剖析母体Treg如何引起感染易感性的分子基础，并确定克服母体Treg抑制所需的李斯特菌特异性毒力决定因素。建立 这些发现的更广泛的适用性，最终的目的将调查是否也发生了压倒性的母体Treg介导的胎儿耐受性的其他病原体，引起产前感染（如疟原虫，E.大肠杆菌、B群链球菌、沙门氏菌、衣原体和巨细胞病毒）。这些实验的完成将揭示母体THP如何导致产前感染易感性，并确定感染诱导的转变如何影响胎儿的发育。 在Treg介导的胎儿耐受中，产前感染对发育中的胎儿造成损伤。

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.