The role of TLR signaling in fetal brain injury from prenatal inflammation

描述(由申请人提供)：感染和炎症仍然是导致妊娠丢失和婴儿发病率和死亡率的重要因素。孕期母体感染是不良神经行为结局的重要风险因素，包括认知迟缓、精神分裂症、自闭症和智力低下。感染孕妇的常见微生物包括大肠杆菌、B组链球菌、支原体和解脲支原体；所有这些病原体都与围产期损伤有关，接触这些微生物会对后代产生长期后果。这些特殊的微生物最有可能通过在宫腔内的定植和/或感染，而不是通过母亲的全身感染，导致围产期发病率。了解了这一更常见的临床情景，我们开发了准确模拟人类宫内感染和炎症的小鼠模型。我们实验室的研究表明，暴露在宫内感染中会导致胎儿和出生后的脑损伤。最近，我们已经证明，即使在低剂量的宫内炎症模型中-子宫内的免疫反应最小-宫腔中的细菌副产物也会导致胎儿和出生后的脑损伤。虽然母体和胎盘单位免疫反应的激活被认为在产前感染所致胎儿脑损伤的发病机制中起着关键作用，但Toll样受体(TLR)信号通路在胎盘感染中的必要性 母亲、胎盘和/或胎儿对炎症所致胎儿脑损伤的影响尚未阐明。在揭示导致产前感染不良后果的先天免疫途径之前，治疗策略是无法开始的。以母体TLR途径为靶点可能是预防不良结局的重要治疗策略；然而，如果病原体或病原体副产物在没有母体免疫反应的情况下可以直接激活胎儿TLR，并且TLR疗法不能到达胎儿间室，则这种方法可能是徒劳的。此外，如果免疫介质激活非TLR通路，无论是在母亲还是胎儿中，靶向TLR信号将无法阻止结果。目前尚不清楚母体和/或胎儿TLR信号是否是暴露于产前炎症所致脑损伤的关键步骤；因此，尚未寻求针对这些途径的直接治疗。我们假设1)胎儿期感染引起的胎儿脑损伤是通过一条共同的途径发生的，而不考虑起始的细菌病原体和/或被激活的特定TLR；2)母体TLR信号对于炎症诱导的脑损伤是充分的，但不是必要的；3)胎儿(和胎盘)TLR信号对于炎症诱导的胎儿脑损伤是足够的。利用TLR途径中的转基因小鼠和胚胎移植技术，我们将创造出母鼠和胎盘单位是不同的遗传型的怀孕母鼠。因此，通过我们的小鼠宫内感染模型和描绘的结果，我们将能够确定母体和胎儿TLR信号在暴露于产前感染后的不良结局中的作用。

DESCRIPTION (provided by applicant): Infection and inflammation remain a significant contributor to pregnancy loss and infant morbidity and mortality. Maternal infections during pregnancy represent a significant risk factor for adverse neurobehavioral outcomes, including cognitive delay, schizophrenia, autism and mental retardation. Common organisms that infect pregnant women include E. coli, Group B streptococcus, Mycoplasma and Ureaplamsa; all of these pathogens are implicated in perinatal injury and exposure to these organisms has been associated with long term consequences for the offspring. These particular organisms are most likely to contribute to perinatal morbidity through colonization and/or infection in the uterine cavity not from systemic infection of the mother. Understanding this more common clinical scenario, we have developed mouse models that accurately mimic intrauterine infection and inflammation in the human. Research from our laboratory has demonstrated that exposure to intrauterine infection results in both fetal and postnatal brain injury. More recently, we have demonstrated that even with a low dose model of intrauterine inflammation-in which there is minimal immune response in the uterus-that bacterial by-products in the uterine cavity can cause fetal and postnatal brain injury. While activation of the immune response in both the mother and feto-placental unit is believed to play a crucial role in the pathogenesis of fetal brai injury from prenatal infection, the necessity of Toll-like receptor (TLR) signaling pathways in the mother, placenta and/or fetus to inflammation-induced fetal brain injury has not been elucidated. Until the innate immune pathways mechanistically responsible for adverse outcomes from prenatal infection are revealed, therapeutic strategies cannot begin. Targeting maternal TLR pathways may be an important therapeutic strategy to prevent adverse outcomes; however, this approach may be for naught if pathogen or pathogen by-products can directly activate fetal TLR in the absence of a maternal immune response and TLR therapies do not reach the fetal compartment. Moreover, if immune mediators activate non- TLR pathways, in either the mother or fetus, targeting TLR signaling would fail to prevent outcomes. It remains unknown whether maternal and/or fetal TLR signaling is a crucial step in brain injury from exposure to prenatal inflammation; as such, directive therapies to these pathways have not been pursued. We hypothesize 1) that fetal brain injury from prenatal infection occurs by a common pathway regardless of the initiating bacterial pathogen and/or the specific TLR that is activated; 2) maternal TLR signaling is sufficient, but not necessary, for inflammation-induced brain injury, and 3) that fetal (and placenta) TLR signaling is sufficient for inflammation-induced fetal brain injury. Using genetically manipulated mice in the TLR pathway and embryo transfer technique, we will create pregnant dams in which the mother and feto-placental unit are divergent genoyptes. Thus, with our mouse model of intrauterine infection and delineated outcomes, we will be able to determine the role of maternal vs. fetal TLR signaling in adverse outcomes after exposure to prenatal infection.