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、感染的持续或复发以及感染的结果。最后一个方面是一个特别的挑战，因为在不同的人中感染相同的病毒，无论病毒载量如何，都可能导致无效、胎儿丧失、畸形或生长异常。根据现有的关于人类感染巨细胞病毒、风疹和细小病毒的数据，我们断言胎盘和病毒因素以及母体免疫影响怀孕期间病毒感染的总体结果。我们的实验模型采用淋巴细胞性脉络膜脑膜炎病毒(LCMV)感染C57BL/6小鼠。该模型的初步数据表明，对LCMV的系统免疫反应，包括在怀孕期间产生抗原特异性记忆T细胞池，与未怀孕状态下没有什么不同。然而，怀孕的动物虽然能够从体循环和几个组织中清除病毒，但在分娩前无法从胎盘中清除病毒，并经历了高流产率。一些完成妊娠并在出生前从感染了病毒但清除了病毒的母亲那里分离出来的胎儿也是病毒阴性。尽管他们的胎盘持续感染，但这是真的。LCMV感染胎盘的机制尚不清楚。此外，现有技术还不能很好地描述母胎界面对LCMV的免疫应答。然而，细胞感染和免疫反应在淋巴组织和外周血中都得到了广泛的研究，这些研究将指导我们的实验方法。我们的假设是，LCMV在胎盘中有特殊的趋向性，这是导致胎盘和全身对LCMV免疫反应明显不同的重要原因。这一应用建议开发和使用新的试剂和系统以及免疫组织化学来描述胎盘局部T细胞对LCMV感染的反应，II)确定母胎界面LCMV感染的细胞和分子后果，以及III)研究系统性感染后支持高病毒载量的胎盘新机制。这一结果将有助于更好地了解该部位的抗原特异性T细胞免疫，并可能指导未来针对导致胎盘持续感染的药物的治疗和疫苗的开发。

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.