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中发现 从非洲到亚洲。 ZIKV已经在全球范围内出现，已经达到大流行水平，扩散到 墨西哥，中美洲，加勒比海和南美。 ZIKV通常会引起轻度疾病，但感染 怀疑孕妇的孕妇在 巴西，从2015年底开始，假定已被感染了以前未知的途径 感染。 ZIKV与胎儿中脑发育异常的关联得到了支持 最近在流产的胎儿和 出生后不久死亡的婴儿。因此，至关重要的是，我们尽可能多地了解ZIKV的复制和 与其宿主相互作用，包括在中枢神经系统的细胞中。 I型IFN反应是早期有效的抗病毒 对病毒入侵的反应可能对限制病毒扩散产生重大影响 在 缺乏I型IFN信号传导的小鼠。中枢神经系统表达低水平的干扰素信号基因与 外围器官表明中枢神经系统可能不太准备限制病毒侵袭。另外，病毒 抑制或逃避宿主免疫反应，以促进宿主的复制并引起 疾病，因此用宿主IFN拮抗作用编码蛋白质。因此，感染的结果 取决于宿主免疫防御和病毒编码的毒力因子的平衡，这可能会有所不同 在病毒和组织类型中。我们已经对IFN信号反应进行了广泛研究 在体外以及中枢神经系统和小鼠的外围的各种细胞类型中的神经脊髓性鼠冠状病毒。 我们建议使用我们的专业知识以及收集的信息，以及我们最近的数据表明 在人类A549细胞中，ZIKV的稳健复制激活了OAS-RNASE L途径和初级 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定差异的假设 I型IFN对ZIKV的反应可能导致胎儿大脑对ZIKV诱导的敏感性 病理。在AIM 1中，我们将研究ZIKV感染的人A549细胞和 CRIPSR/CAS9设计的基因敲除A549细胞以及主要的鼠神经元和神经胶质细胞培养物。在 AIM 2我们将研究胚胎和新生小鼠的体内ZIKV复制和IFN反应。之上 完成这些目标的完成，我们将了解I型IFN对ZIKV在体外的反应 人类细胞以及鼠CNS细胞。我们还将了解更多有关发育中鼠标中IFN信号的信息 zikv从感染的母亲那里传播。这两种方法的结合将有助于理解 IFN信号传导对ZIKV感染和扩散的影响，在更长远的长期中确定了目标的目标 制定治疗ZIKV诱发疾病的治疗策略。