Role of type I interferon signaling in Zika virus infection of the brain

I 型干扰素信号在寨卡病毒大脑感染中的作用

• 批准号: 9256709
• 负责人: Susan R Weiss
• 金额: $ 20.13万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256709
• 关键词: A549; Aborted Fetus; Address; Adult; Affect; Africa; Amniotic Fluid; Animal Model; Antigens; Antiviral Agents; Antiviral Response; Asia; Autopsy; Birth; Blood; Brain; Brazil; CRISPR/Cas technology; Caribbean region; Cell Culture Techniques; Cells; Central America; Central Nervous System Infections; Coronavirus; Culicidae; Data; Detection; Development; Disease; Double-Stranded RNA; Embryo; Emergency Situation; Engineered Gene; Engineering; Epidemic; Equilibrium; Fetal Development; Fetus; Flavivirus; French Polynesia; Gene Expression; Genes; High-Throughput RNA Sequencing; Histocompatibility Testing; Host Defense; Human; Immune; Immune response; In Vitro; Infection; Insecta; Interferon Type I; Interferon-alpha; Interferons; Island; Knock-out; Knowledge; Learning; Length; Ligase; Liver; Mexico; Microcephaly; Microglia; Micronesia; Monkeys; Mothers; Mus; Neonatal; Nerve Degeneration; Neuraxis; Neuroglia; Neurologic; Neurons; Newborn Infant; Organ; Outcome; Pathology; Pathway interactions; Peripheral; Placenta; Play; Predisposition; Pregnancy; Pregnant Women; Primary Infection; Production; Proteins; RNA Sequences; Reporting; Ribonucleases; Role; Route; Signal Pathway; Signal Transduction; Skin; South America; Spleen; Testing; Therapeutic; Time; Tissues; Tropism; Uganda; Viral; Viral Genome; Virulence Factors; Virus; Virus Diseases; Virus Replication; West Nile virus; Wild Type Mouse; World Health Organization; Zika Virus; brain cell; brain tissue; cell type; design; eIF-2 Kinase; fetal; in vivo; information gathering; mortality; neonatal brain; neonate; nervous system disorder; neurotropic virus; nonhuman primate; oligoadenylate; pandemic disease; particle; pregnant; response; therapeutic development; transcriptome; transmission process; viral RNA

Zika virus (ZIKV) is an insect borne flavivirus which until recently was found within a narrow equatorial belt from Africa to Asia. ZIKV has emerged across the globe and has reached pandemic levels, spreading to Mexico, Central America, the Caribbean and South America. While ZIKV usually causes mild disease, infection of pregnant women has been suspected to cause a significant increase in babies born with microcephaly in Brazil, starting in late 2015, presumed to have become infected transplacentally a previously unknown route of infection. The association of ZIKV with abnormal brain development in the fetus has been supported by the recent detection of ZIKV RNA sequences and antigens along with neurodegeneration in aborted fetuses and babies that died soon after birth. Thus it is vital that we learn as much as possible of how ZIKV replicates and interacts with its host, including in cells of the CNS. The type I IFN response is an early potent antiviral response to viral invasion that can have a major impact on restricting virus spread as evidenced by significantly increased virus replication and rapid mortality as well as loss of organ tropism barriers observed in mice lacking type I IFN signaling. The CNS expresses low levels of interferon signaling genes compared to peripheral organs suggesting the CNS may be less prepared to restrict viral invasion. In addition, viruses suppress or evade the host immune response in order to facilitate their replication within a host and cause disease and therefore encode proteins with host IFN antagonist activities. The outcome of infection therefore depends on the balance of host immune defenses and virus encoded virulence factors and this can differ among viruses and tissue types. We have carried out extensive studies of IFN signaling responses to neurovirulent murine coronavirus in various cell types in vitro as well as in the CNS and the periphery of mice. We propose to use our expertise as well as information gathered, along with our recent data demonstrating robust replication of ZIKV in human A549 cells where it activates the OAS-RNase L pathway and in primary murine neuronal and glial cell cultures to test the hypothesis that cell type and tissue specific differences in the type I IFN response to ZIKV may contribute to susceptibility of the fetal brain to ZIKV-induced pathology. In Aim 1 we will investigate the IFN signaling pathways during ZIKV infected human A549 cells and CRIPSR/Cas9 engineered knockout A549 cells as well as primary murine neuronal and glial cell cultures. In Aim 2 we will investigate ZIKV replication and IFN response in vivo in embryonic and neonatal mice. Upon completion of these aims we will have gained an understanding of the type I IFN response to ZIKV in vitro in human cells as well as murine CNS cells. We will also know more about IFN signaling in the developing mouse embryo and spread of ZIKV from infected mothers. These two approaches combined will aid in understanding the impact of IFN signaling on ZIKV infection and spread and in the more long term identify targets for the development of therapeutic strategies to treat ZIKV-induced disease.

寨卡病毒 (ZIKV) 是一种昆虫传播的黄病毒，直到最近才在狭窄的赤道带内发现 从非洲到亚洲。 ZIKV 已在全球范围内出现，并已达到大流行程度，并蔓延到 墨西哥、中美洲、加勒比海和南美洲。虽然 ZIKV 通常会引起轻微的疾病，但感染 孕妇被怀疑导致出生时患有小头畸形的婴儿显着增加 巴西从 2015 年底开始，推测已通过胎盘途径感染，这是一种以前未知的途径 感染。 ZIKV 与胎儿大脑发育异常之间的关联得到了以下研究的支持 最近检测到 ZIKV RNA 序列和抗原以及流产胎儿和神经退行性疾病 出生后不久就死亡的婴儿。因此，我们尽可能多地了解 ZIKV 如何复制和传播是至关重要的。 与其宿主相互作用，包括中枢神经系统细胞。 I 型干扰素反应是一种早期有效的抗病毒药物 对病毒入侵的反应可能对限制病毒传播产生重大影响，如下所示 病毒复制显着增加，死亡率迅速上升，并且器官趋向性屏障丧失 缺乏 I 型 IFN 信号传导的小鼠。与中枢神经系统相比，中枢神经系统表达低水平的干扰素信号基因 外周器官表明中枢神经系统可能尚未做好限制病毒入侵的准备。此外，病毒 抑制或逃避宿主免疫反应，以促进其在宿主内复制并导致 疾病，因此编码具有宿主干扰素拮抗剂活性的蛋白质。因此感染的结果 取决于宿主免疫防御和病毒编码毒力因子的平衡，这可能会有所不同 病毒和组织类型之间。我们对 IFN 信号反应进行了广泛的研究 体外各种细胞类型以及小鼠中枢神经系统和外周细胞中的神经毒力鼠冠状病毒。 我们建议利用我们的专业知识和收集的信息，以及我们最近的数据证明 ZIKV 在人 A549 细胞中的稳健复制，激活 OAS-RNase L 通路，并且在原代细胞中 小鼠神经元和神经胶质细胞培养物，以检验细胞类型和组织特异性差异的假设 I 型干扰素对 ZIKV 的反应可能导致胎儿大脑对 ZIKV 诱导的易感性 病理。在目标 1 中，我们将研究 ZIKV 感染人类 A549 细胞期间的 IFN 信号传导途径，以及 CRIPSR/Cas9 工程敲除 A549 细胞以及原代小鼠神经元和神经胶质细胞培养物。在 目标 2 我们将研究 ZIKV 在胚胎和新生小鼠体内的复制和 IFN 反应。之上 完成这些目标后，我们将了解 I 型 IFN 在体外对 ZIKV 的反应 人类细胞以及小鼠中枢神经系统细胞。我们还将更多地了解发育中小鼠中的 IFN 信号传导 受感染母亲的胚胎和 ZIKV 传播。这两种方法结合起来将有助于理解 IFN 信号传导对 ZIKV 感染和传播的影响，并从长远来看确定治疗目标 开发治疗寨卡病毒引起的疾病的治疗策略。