Placental Immunity to LCMV

胎盘对 LCMV 的免疫

• 批准号: 7355991
• 负责人: ELIZABETH A. BONNEY
• 金额: $ 27.84万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7355991
• 关键词: Abortion Rates; Activities of Daily Living; Acute; Affect; Alphavirus; Animals; Antigens; Antiviral Agents; Area; Biological Assay; Birth; Blood Circulation; C57BL/6 Mouse; CD8B1 gene; Cells; Cessation of life; Chickenpox; Class; Cytomegalovirus; Data; Development; Drug effect disorder; Exhibits; Experimental Models; Face; Failure; Fetus; Future; Generations; Growth; Histocytochemistry; Human; Immune; Immune response; Immunity; In Situ; Individual; Infection; Kinetics; Laboratories; Lead; Localized; Lymphoid Tissue; MHC Class I Genes; Maternal-Fetal Exchange; Measures; Mediating; Memory; Modeling; Molecular; Mothers; Mus; Natural Immunity; Necrosis; Numbers; Outcome; Parvovirus; Patient currently pregnant; Peripheral; Personal Satisfaction; Placenta; Pregnancy; Prevention; Reagent; Research Personnel; Rubella; Site; System; Systemic infection; T memory cell; T-Lymphocyte; Technology; Testing; Thrombosis; Time; Tissues; Tropism; Tumor Necrosis Factor Ligand Superfamily Member 6; Uterus; Vaccines; Viral; Viral Load result; Viral Proteins; Virus; Virus Diseases; West Nile virus; base; cytokine; experience; fetal; genetic selection; genetic variant; in vivo; malformation; novel; peripheral blood; placental transfer; programs; receptor; response

We continue to be intrigued by several aspects of viral infection of the humanplacenta, 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 Lymphocyticchoriomeningitis virus (LCMV) infection in C57BL/6 mice. Preliminary data in this model suggests that the systemic immuneresponse 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 immuneresponse 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 forLCMV 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 novelplacenta!mechanism supporting high viral load after systemic infection The results will lead to a better understanding of antigen specific T cell immunityat this site and may guide development of future treatment and vaccines against agents causing persistent infectionof the placenta.

我们继续对人类胎盘病毒感染的几个方面感兴趣，包括机制 感染的程度、感染的选择性、感染的持续或复发以及感染的结果。这 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，独立于 病毒载量，可与无效，或胎儿丧失，畸形或生长异常有关。基于 关于人类感染巨细胞病毒、风疹和细小病毒的现有数据，我们断言胎盘 病毒因素以及母亲的免疫力影响着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。 该模型中的初步数据表明，对LCMV的系统免疫反应，包括产生 怀孕期间的抗原特异性记忆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， 孕妇在分娩前无法清除胎盘中的病毒，流产率很高。一些人 从被感染但清除了病毒的母亲那里分离出来的胎儿，完成妊娠并在出生前分离出来， 病毒也是阴性的。尽管他们的胎盘持续感染，但这是真的。人的感染 LCMV胎盘的发病机制尚不清楚。此外，对LCMV的免疫应答在 现有的技术还不能很好地描述母胎界面。然而，无论是手机还是手机 对淋巴组织和外周血中的感染和免疫反应进行了广泛的研究， 这些研究将指导我们的实验方法。我们的假设是LCMV有特殊的取向。 在胎盘中，这对胎盘和全身的明显差异有显著的贡献 对LCMV的免疫应答。这项申请建议开发和使用新的试剂和系统 和免疫组织化学以描述胎盘局部T细胞对LCMV感染的反应 确定母胎界面LCMV感染的细胞和分子后果 研究一种新的胎盘机制，在系统感染后支持高病毒载量 有助于更好地了解这一部位的抗原特异性T细胞免疫，并可能指导 针对导致持续胎盘感染的药物的未来治疗和疫苗。