Placental Immunity to LCMV

描述（由申请人提供）：我们继续对人类胎盘病毒感染的几个方面感兴趣，包括感染机制、感染的选择性、感染的持续性或复发以及感染的结局。这最后一个方面是一个特别的挑战，因为在不同个体中感染相同的病毒，与病毒载量无关，可能与无影响，或胎儿丢失，畸形或生长异常有关。根据现有的数据，人类感染巨细胞病毒，风疹，细小病毒，我们断言，胎盘和病毒因素，以及母体免疫力影响的总体结果病毒感染在怀孕期间。我们的实验模型使用C57 BL/6小鼠中的淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染。该模型中的初步数据表明，妊娠期间对LCMV的全身免疫应答（包括抗原特异性记忆T细胞库的产生）与非妊娠状态没有不同。然而，妊娠动物虽然能够从体循环和几种组织中清除病毒，但在分娩前无法从胎盘中清除病毒，流产率很高。一些胎儿，完成妊娠，并在出生前从感染但清除病毒的母亲中分离出来，也是病毒阴性。这是真的，尽管他们的胎盘持续感染。胎盘感染LCMV的机制尚不清楚。此外，在母胎界面对LCMV的免疫应答尚未用现有技术很好地表征。然而，细胞感染和免疫反应已在淋巴组织和外周血中被广泛研究，这些研究将指导我们的实验方法。我们的假设是LCMV在胎盘中有特殊的嗜性，这对胎盘和全身对LCMV的免疫应答的明显差异有重要作用。本申请提出了开发和使用新的试剂和系统以及免疫组织化学，以i）描绘对胎盘LCMV感染的局部T细胞应答，ii）确定母胎界面处LCMV感染的细胞和分子后果，以及iii）研究支持全身感染后高病毒载量的一种新的胎盘机制结果将导致对抗原特异性T细胞免疫的更好理解并可能指导未来治疗和疫苗的开发，以对抗导致胎盘持续感染的病原体。

DESCRIPTION (provided by applicant): We continue to be intrigued by several aspects of viral infection of the human placenta, including mechanism of infection, selectivity of infection, persistence or reemergence of infection, and outcome of infection. This last aspect is a particular challenge as infection with the same virus in different individuals, independent of viral load, can be associated with no effect, or fetal loss, malformation or growth abnormalities. Based on existing data about human infection with Cytomegalovirus, Rubella, and Parvovirus we assert that placental and viral factors, as well as maternal immunity affect the overall outcome of viral infection during pregnancy. Our experimental model uses Lymphocytic choriomeningitis virus (LCMV) infection in C57BL/6 mice. Preliminary data in this model suggests that the systemic immune response to LCMV, including generation of an antigen-specific memory T-cell pool during pregnancy is not different than in a non-pregnant state. However, pregnant animals, although able to clear the virus from the systemic circulation and several tissues, were not able to clear virus from the placenta before delivery and experienced a high rate of abortion. Some fetuses, completing gestation and isolated just before birth from mothers who were infected but cleared virus, also were negative for virus. This was true despite continued infection of their placentas. Infection of the placenta with LCMV is poorly understood mechanistically. Moreover, the immune response to LCMV at the maternal-fetal interface has not been well characterized with the existing technology. However, both cellular infection and immune response have been extensively studied in lymphoid tissues and peripheral blood, and these studies will guide our experimental approach. Our hypothesis is that there is special tropism for LCMV in the placenta, and that this contributes significantly to the apparent difference in placental and systemic immune responses to LCMV. This application proposes development and use of new reagents and systems and immuno-histochemistry to i) delineate the local T cell response to LCMV infection of the placenta ii) determine the cellular and molecular consequences of LCMV infection at maternal-fetal interface and iii) investigate a novel placental mechanism supporting high viral load after systemic infection The results will lead to a better understanding of antigen specific T cell immunity at this site and may guide development of future treatment and vaccines against agents causing persistent infection of the placenta.