Determining how macrophages regulate immunity to Zika virus infection at the maternal-fetal interface

确定巨噬细胞如何调节母胎界面对寨卡病毒感染的免疫力

基本信息

批准号：
9882936
负责人：
Rana Chakraborty
金额：
$ 44.68万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9882936
关键词：
Address Adult Americas Antiviral Agents Antiviral Response Birth Blood Cell Death Cells Chorionic villi Chronic Congenital Abnormality Cytomegalovirus Development Epidemic Evolution Fetal Development First Pregnancy Trimester Flavivirus Genes Genetic Transcription Guillain-Barré Syndrome HIV-1 Hepatitis B Hepatitis C virus Herpes Simplex Infections Homeostasis Human Human Parvovirus B19 Immune Immune response Immune signaling Immunity Immunology In Vitro Infant Infection Inflammatory Integration Host Factors Interferon-alpha Interferons Kinetics Knowledge Link Maintenance Maternal-Fetal Exchange Microcephaly Molecular Biology Mothers Mus Neonatal Organ Pathway interactions Pattern recognition receptor Placenta Play Pregnancy Pregnant Women Public Health Publishing Receptor Signaling Risk Role Rubella Second Pregnancy Trimester Signal Pathway Signal Transduction Spontaneous abortion Stimulator of Interferon Genes Systems Biology Therapeutic Third Pregnancy Trimester Tissues Tretinoin Tropism Up-Regulation Vaccines Villus Viral Viral Antigens Virion Virus Diseases Virus Replication Woman ZIKV infection Zika Virus adverse pregnancy outcome base brain abnormalities cell type cytokine fetal fetal infection histiocyte in utero in vivo innate immune mechanisms insight interdisciplinary approach macrophage monocyte mosquito-borne permissiveness placental infection pregnant programs receptor response therapeutic target vaccine development viral RNA viral transmission virology

项目摘要

ABSTRACT The placenta is characterized by intimate contact between the maternal blood and fetal chorionic villi. This organ is a target for rubella, cytomegalovirus, herpes simplex, HIV-1, hepatitis B and C viruses and parvovirus B19 infection, by either direct or contiguous infection of placental cell layers, virion passage through a breach or by cell-associated transport. Most recently, Zika virus (ZIKV), a mosquito-borne flavivirus of significant public health concern in the Americas, was found to transmit from an infected mother to the developing fetus in utero , resulting in adverse pregnancy outcomes characterized by fetal brain abnormalities and microcephaly. The greatest risk of serious fetal sequelae is associated with ZIKV infection early in pregnancy, suggesting enhanced tropism for placental cells during the first- and second-trimester. However the mechanism by which ZIKV establishes placental and fetal infection is poorly understood. We seek to fill this gap in knowledge and develop a deeper mechanistic understanding for how macrophages in the maternal-fetal compartment maintain immune homeostasis and restrict ZIKV transmission to the developing fetus. ZIKV antigen has been detected in chronic villi, specifically within placental macrophages or Hofbauer cells (HCs) and histiocytes from women who gave birth to infants with microcephaly or had active ZIKV infection during pregnancy. ZIKV RNA has also been isolated from placental tissue in humans and from pregnant mice infected with ZIKV. Several studies, including one recently published by our group, identified HCs as target cells of viral infection in vivo and in vitro. We showed that primary human HCs isolated from full-term placentae are permissive to productive infection by a contemporary strain of ZIKV, PRVABC59 (PR 2015). Upon ZIKV infection, HCs produced IFN-α and pro-inflammatory cytokines, however, we observed little to no cell death. Our findings were the first to identify a permissive cell type for ZIKV infection in the placenta, however, it is still unclear what role decidual or fetal monocyte-derived macrophages play during ZIKV infection and whether these placental cells dynamically change during pregnancy to program more potent antiviral responses to virus infection later in pregnancy. Based on our preliminary studies, our proposal will address the central hypothesis that macrophages in the maternal-fetal compartment (decidual, placental and fetal) in early gestation are more permissive for ZIKV infection and replication as compared to late-gestation macrophages, directly corresponding to reduced potency of cell autonomous antiviral immune signaling. Our proposal is divided into two specific aims that seek: 1) To define the dynamics of innate immune signaling in macrophages at the maternal-fetal interface during pregnancy; and 2) To determine how macrophages in the maternal-fetal compartment control ZIKV infection during pregnancy. These studies will provide new insights to ZIKV immunity in humans, elucidate mechanisms of innate immune control within the placenta and contribute to development of urgently needed effective antiviral therapeutics and vaccines.

抽象的胎盘的特点是母体血液与胎儿绒毛膜绒毛密切接触。该器官是风疹、巨细胞病毒、单纯疱疹、HIV-1、乙型和丙型肝炎病毒以及细小病毒的目标 B19 感染，通过直接或连续感染胎盘细胞层，病毒粒子通过缺口最近，寨卡病毒（ZIKV）是一种通过蚊媒传播的黄病毒。美洲的健康问题，被发现是通过受感染的母亲传播的使胎儿在子宫内发育 , 导致以胎儿大脑异常和小头畸形为特征的不良妊娠结局。严重胎儿后遗症的最大风险与怀孕早期感染寨卡病毒有关，这表明然而，在妊娠早期和中期，胎盘细胞的趋向性增强。人们对 ZIKV 引起的胎盘和胎儿感染知之甚少，我们试图填补这一知识空白。对母胎室中的巨噬细胞如何维持已检测到免疫稳态并限制 ZIKV 传播给发育中的胎儿。在慢性绒毛中，特别是在女性的胎盘巨噬细胞或霍夫鲍尔细胞 (HC) 和组织细胞中曾生育过小头畸形婴儿或在怀孕期间感染过 ZIKV RNA 的人也有感染。已从人类胎盘组织和感染 ZIKV 的怀孕小鼠中分离出来。包括我们小组最近发表的一篇文章，将 HC 确定为体内和体内病毒感染的靶细胞我们表明，从足月胎盘中分离出的原代人类 HC 具有生产性。感染 ZIKV 病毒株 PRVABC59 (PR 2015)。感染 ZIKV 后，HC 会产生 IFN-α。然而，我们的发现几乎没有观察到细胞死亡。确定了胎盘中 ZIKV 感染的允许细胞类型，然而，目前尚不清楚蜕膜或胎儿单核细胞来源的巨噬细胞在 ZIKV 感染期间发挥作用以及这些胎盘细胞是否动态变化怀孕期间的改变，以便在怀孕后期对病毒感染产生更有效的抗病毒反应。根据我们的初步研究，我们的建议将解决以下中心假设：巨噬细胞在妊娠早期的母胎室（蜕膜、胎盘和胎儿）更容易感染 ZIKV 与妊娠晚期巨噬细胞相比，感染和复制，直接对应于减少我们的建议分为两个具体目标： 1）定义母胎界面巨噬细胞先天免疫信号的动态怀孕；2) 确定母胎室中的巨噬细胞如何控制 ZIKV 感染这些研究将为人类 ZIKV 免疫提供新的见解，阐明机制。胎盘内的先天免疫控制，并有助于开发迫切需要的有效抗病毒疗法和疫苗。