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

• 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
• 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

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 斑点的特征是母亲血液和胎儿绒毛膜绒毛之间的亲密接触。这 器官是风疹，巨细胞病毒，单纯疱疹，HIV-1，乙型肝炎和C病毒以及细小病毒的目标 B19感染，通过直接或连续感染的胎盘层感染，病毒率通过突破 或通过与细胞相关的转运。最近，Zika Virus（Zikv），蚊子传播的大型公众的黄病毒 在美洲的健康问题被发现从感染的母亲传播 到子宫内发育的胎儿 ，，，， 导致以胎儿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初期的ZIKV感染有关 在头孕期和二年中，占地细胞的向流增强。但是，该机制的机制 ZIKV建立斑点和胎儿感染的理解很少。我们试图在知识中填补这一空白， 对母亲室中的巨噬细胞如何保持 免疫稳态并将ZIKV传播限制为发育中的胎儿。 ZIKV抗原已被检测到 在慢性绒毛中，特别是在Placenal巨噬细胞或Hofbauer细胞（HCS）和女性组织细胞中 在怀孕期间生下了小头畸形的婴儿或活跃的ZIKV感染。 zikv rna也有 我们与人类的胎盘组织和感染了ZIKV感染的怀孕小鼠分离。几项研究， 包括我们小组最近发表的一份，将HCS确定为体内病毒感染的靶细胞 体外。我们表明，从足月片段中分离出的原代人HC是允许的。 当代ZIKV菌株的感染，Prvabc59（PR 2015）。 ZIKV感染后，HCS产生IFN-α 但是，促炎性细胞因子，我们几乎没有观察到细胞死亡。我们的发现是第一个 但是，识别宽松感染的宽敞细胞类型，但是，仍然不清楚角色的决定性或 ZIKV感染期间胎儿单核细胞衍生的巨噬细胞发挥作用，以及这些斑点细胞是否动态 怀孕期间的变化以编程对病毒感染的更多潜在抗病毒反应。 基于我们的初步研究，我们的建议将解决以下核心假设。 早期妊娠中的母亲室内室（decidal，blopenal和胎儿）更允许ZIKV 与晚期妊娠巨噬细胞相比，感染和复制直接对应于减少 细胞自主抗病毒免疫信号的效力。我们的建议分为两个特定的目标： 1）定义在巨噬细胞中巨噬细胞中天赋的免疫信号的动力学 怀孕; 2）确定母亲区室中的巨噬细胞如何控制ZIKV感染 怀孕期间。这些研究将为人类的ZIKV免疫提供新的见解，阐明机制 斑点内的先天免疫控制，并有助于迫切需要开发 抗病毒疗法和疫苗。