MECHANISMS OF SCHISTOSOME ASSOCIATED TROPHOBLAST INJURY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这项建议的总体目标是了解血吸虫感染妇女不良妊娠结局的机制(S)。 健康、成功的妊娠的特点是胎盘微环境偏向T辅助细胞2型(Th2)细胞因子环境[1，2]。人类感染血吸虫病会导致在体循环中检测到的促炎细胞因子的产生，包括肿瘤坏死因子-β[11-15]、白介素6[16]和干扰素-β[12，17]。在人类研究中，这些细胞因子中的每一个都与胎儿生长受限有关[18-21]。 在对居住在菲律宾日本血吸虫流行区的N=97名孕妇的初步研究中，我们证明，在调整了母亲的身高、胎龄和地理蠕虫感染(N=60，P=0.06)后，中等或高强度日本血吸虫感染的妇女生下的新生儿体重比低强度或未感染的妇女低460克。此外，与未感染的女性相比，中度感染的女性胎盘血液促炎细胞因子水平升高，滋养层细胞促炎细胞因子的产生增加，滋养层细胞凋亡增加。 在这项建议中，我们将利用曼氏血吸虫的小鼠模型来了解血吸虫感染过程中滋养细胞激活的机制。我们假设，裂殖体将秘密的配体进入母体循环，激活滋养层细胞上的Toll样受体(TLRs)。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall goal of this proposal is to understand the mechanism(s) of poor pregnancy outcome in schistosome infected women. Healthy, successful pregnancies are characterized by a placental microenvironment that is biased toward a T-helper cell type 2 (Th2) cytokine milieu [1, 2]. Human infection with schistosomiasis results in the elaboration of pro-inflammatory cytokines including TNF-? [11-15], IL-6 [16], and IFN-? [12, 17] that are detected in the systemic circulation. Each of these cytokines has been implicated in fetal growth restriction in human studies [18-21]. In a pilot study in N=97 pregnant women living in a Schistosoma japonicum endemic area of the Philippines, we demonstrated that women with moderate or high intensity S. japonicum infection gave birth to newborns with birth weights that were 460 grams lower than women with low intensity or no infection, after adjusting for maternal height, gestational age, and geo-helminth infections (N=60, P = 0.06). Furthermore, moderately infected women had increased placental blood pro-inflammatory cytokine levels, increased trophoblast production of pro-inflammatory cytokines, and increased trophoblast apoptosis compared to uninfected women. In this proposal, we will utilize a murine model of S. mansoni to understand the mechanisms of trophoblast activation during schistosome infection. We hypothesize that schistsomes secret ligands into the maternal circulation that activate Toll-like receptors (TLRs) on trophoblasts.