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

• 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
• 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

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.

项目摘要 寨卡病毒（ZIKV）是一种蚊媒黄病毒，最初于1947年在乌干达发现， 其病史与轻度自限性疾病有关。这在最近和正在进行的ZIKV中发生了变化 在南太平洋和拉丁美洲爆发了新的传播方式（即性传播）， 和在子宫内），以及意外的疾病表现（包括出生缺陷和格林-巴利综合征 综合征）。ZIKV感染的这些严重表现都涉及病毒侵入通常 受到解剖屏障的保护，包括中枢神经系统、睾丸和胎儿。 车厢了解决定ZIKV组织嗜性的病毒和宿主因素对于ZIKV的治疗至关重要。 评估新出现的ZIKV毒株在新宿主环境中的致病潜力。在本提案中，我们 将采用一种新的ZIKV反向遗传学系统来实验性地测试基因改变的假设， 目前在拉丁美洲流行的ZIKV毒株赋予增强的毒力。特别是，我们将重点关注 病毒体包膜蛋白中的N-连接的糖基化，因为这是公认的作为病毒的毒力决定因素。 ZIKV的当代爆发株与历史株之间存在差异。自从小说以来 组织嗜性可能导致ZIKV感染的新表现，我们将研究干扰素的作用 λ（IFN-λ）在维持ZIKV组织嗜性屏障中的作用，包括血脑屏障、胎盘和 支持细胞屏障，如先前西尼罗河病毒神经侵袭所示。我们会感染老鼠， 缺乏IFN-L受体，并比较中枢神经系统，胎儿室，睾丸， 和眼睛，不受专门屏障保护的组织和野生型小鼠。相反，我们将 感染缺乏IFN-ab受体的小鼠，其产生高病毒载量和组织传播， 重组IFN-L蛋白，并确定这是否导致ZIKV的屏障收紧和限制 入侵由于IFN-L蛋白已成功用于治疗丙型肝炎的II期临床试验 由于ZIKV病毒感染，该方法将提供治疗严重ZIKV感染的潜在方法。总之，我们的 研究将揭示ZIKV组织嗜性的关键病毒和宿主决定因素，了解ZIKV组织嗜性的关键方面， 在拉丁美洲目前的疫情中观察到ZIKV感染的严重表现。