Viral and host determinants of Zika virus tissue tropism

寨卡病毒组织趋向性的病毒和宿主决定因素

基本信息

批准号：
9264855
负责人：
Helen Lazear
金额：
$ 22.8万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-11-10 至 2018-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264855
关键词：
Anatomy Biological Assay Blood Blood - brain barrier anatomy Brain Brazil Caribbean region Cell Culture Techniques Cells Collaborations Congenital Abnormality Country Culicidae Digestion Disease Disease Outbreaks Disease model Environment Exanthema Eye Fetus Fever Flavivirus Guillain-Barré Syndrome Hepatitis C Therapy IFNAR1 gene Immune Integration Host Factors Interferons Intervention Invaded Kidney Laboratories Latin America Link Measures Methods Monoclonal Antibodies Mus Mutation Neuraxis Neurologic Pathogenesis Pathogenicity Pattern Peripheral Phase II Clinical Trials Phenotype Placenta Polynesia Polysaccharides Protein Glycosylation Proteins Publishing Recombinants Recording of previous events Reporting Research Retina Role Sequence Analysis Serum Signal Transduction Site Spinal Cord Spleen System Testing Testis Tissues Uganda Viral Viral Envelope Proteins Viral Load result Viremia Virion Virulence Virus Virus Diseases Virus Replication West Nile virus Wild Type Mouse Zika Virus antiviral immunity combat env Gene Products fetal glycosylation in utero interferon-alpha B lymph nodes mouse model mutant nervous system disorder novel placental infection pregnant programs receptor reverse genetics sertoli cell tissue tropism transmission process virus genetics virus pathogenesis

项目摘要

Project Summary Zika virus (ZIKV), a mosquito-borne flavivirus, was originally discovered in Uganda in 1947, and for nearly all of its history has been associated with mild self-limited illness. This changed during recent and ongoing ZIKV outbreaks in the South Pacific and Latin America, which have revealed new modes of transmission (i.e. sexual and in utero), as well as unexpected disease presentations (including birth defects and Guillain-Barré syndrome). These severe manifestations of ZIKV infection all involve the virus invading tissues that ordinarily are protected by anatomic barriers, including the central nervous system, the testes, and the fetal compartment. Understanding the viral and host factors that determine ZIKV tissue tropism is critical for evaluating the pathogenic potential of emerging ZIKV strains in new host environments. In this proposal, we will employ a new ZIKV reverse genetics system to experimentally test the hypothesis that genetic changes in the ZIKV strains currently circulating in Latin America confer enhanced virulence. In particular, we will focus on N-linked glycosylation in the virion envelope protein, as this is well-established as a virulence determinant in other flaviviruses and differs between contemporary outbreak strains of ZIKV and historical ones. Since novel tissue tropism may contribute to new manifestations of ZIKV infection, we will investigate the role of interferon lambda (IFN-λ) in maintaining barriers to ZIKV tissue tropism, including the blood-brain barrier, placenta, and sertoli cell barrier, as has been shown previously for West Nile virus neuroinvasion. We will infect mice that lack the IFN-L receptor and compare ZIKV viral loads in the central nervous system, fetal compartment, testes, and eyes to tissues that are not protected by specialized barriers and to wild-type mice. Conversely, we will infect mice that lack the IFN-ab receptor, which develop high viral loads and tissue dissemination, with recombinant IFN-L protein and determine whether this results in barrier tightening and restriction of ZIKV invasion. As IFN-L protein has been used successfully in phase II clinical trials as a therapy for hepatitis C virus infection, this approach would provide a potential method to treat severe ZIKV infection. Altogether, our studies will reveal key viral and host determinants of ZIKV tissue tropism, key aspects of understanding the severe manifestations of ZIKV infection observed in the current outbreak in Latin America.

项目概要寨卡病毒 (ZIKV) 是一种蚊媒黄病毒，最初于 1947 年在乌干达发现，几乎所有地区都发现了寨卡病毒 (ZIKV)。它的历史与轻度自限性疾病有关，这种情况在最近和持续的寨卡病毒期间发生了变化。南太平洋和拉丁美洲的疫情暴发揭示了新的传播模式（即和子宫内），以及意外的疾病表现（包括出生缺陷和吉兰-巴利综合征） ZIKV 感染的这些严重表现都涉及病毒侵入通常的组织。受到解剖学屏障的保护，包括中枢神经系统、测试和胎儿了解决定 ZIKV 组织趋向性的病毒和宿主因素对于预防 ZIKV 至关重要。在本提案中，我们评估了新出现的 ZIKV 毒株在新宿主环境中的致病潜力。将采用新的 ZIKV 反向遗传学系统来通过实验检验基因变化的假设目前在拉丁美洲流行的 ZIKV 毒株具有更强的毒力，我们将重点关注。病毒粒子包膜蛋白中的 N 连接糖基化，因为这已被确定为病毒的毒力决定因素与其他黄病毒不同，当代爆发的 ZIKV 病毒株与历史上的 ZIKV 病毒株之间存在差异。组织向性可能导致ZIKV感染的新表现，我们将研究干扰素的作用 λ (IFN-λ) 维持 ZIKV 组织趋向性屏障，包括血脑屏障、胎盘和支持细胞屏障，正如之前西尼罗河病毒神经侵入所显示的那样，我们将感染小鼠。缺乏 IFN-L 受体并比较中枢神经系统、胎儿室、测试中的 ZIKV 病毒载量，以及不受特殊屏障保护的组织和离线野生型小鼠的眼睛。感染缺乏 IFN-ab 受体的小鼠，这些小鼠会产生高病毒载量和组织传播重组 IFN-L 蛋白，并确定这是否会导致屏障收紧和限制 ZIKV 由于IFN-L蛋白已成功用于治疗丙型肝炎的II期临床试验。病毒感染，这种方法将为治疗严重的 ZIKV 感染提供一种潜在的方法。研究将揭示 ZIKV 组织趋向性的关键病毒和宿主决定因素、了解 ZIKV 的关键方面在拉丁美洲当前的疫情中观察到 ZIKV 感染的严重表现。