Innate antiviral defense against Vaginal transmission of ZIKA virus

针对寨卡病毒阴道传播的先天抗病毒防御

• 批准号: 9320403
• 负责人: AKIKO IWASAKI
• 金额: $ 25.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-06 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9320403
• 关键词: Aedes; Antiviral Agents; Antiviral resistance; Brain; Centers for Disease Control and Prevention (U.S.); Cerebellum; Clinical; Conceptions; Culicidae; Data; Defense Mechanisms; Female; Fetal Growth Retardation; Fetus; Foundations; Genes; Host resistance; Human; IRF3 gene; Infection; Interferons; Microcephaly; Modeling; Mucous Membrane; Mus; Partner in relationship; Pathogenesis; Pathway interactions; Predisposition; Pregnancy; Pregnancy Outcome; Pregnant Women; Preventive Intervention; Preventive measure; Role; Route; Seminal fluid; Sexual Transmission; Signal Pathway; Symptoms; Testis; Therapeutic Intervention; Vagina; Vertical Disease Transmission; Viral Load result; Viremia; Virus Diseases; Virus Replication; Zika Virus; abortion; cell type; design; fetal; genetic signature; immunological intervention; male; men; mouse model; pregnant; prevent; receptor; reproductive tract; sensor; subcutaneous; transcription factor; transmission process; type I interferon receptor; vaginal transmission; viral transmission; virtual

Project Summary While Zika virus (ZIKV) is well known for its transmission through the Aedes mosquitoes, recent evidence highlights sexual contact with an infected partner as another important route of transmission. There have been multiple confirmed and suspected cases of sexual transmission in humans, all of which involve transmission from infected men to their female partners through vaginal intercourse (1-7). ZIKV has been detected in semen of infected men (4, 6, 8). Collectively, these studies indicate that sexual transmission from infected male to uninfected female occurs in humans. An important clinical concern is whether ZIKV can be transmitted sexually in pregnant women, and what the consequence of such infections may be on the outcome of pregnancy. The CDC urges men with ZIKV disease to wait at least 6 months after symptom onset to attempt conception (5). However, the consequences of sexual transmission of ZIKV during pregnancy are unknown. Three recent studies using the mouse model of ZIKV have revealed that type I interferon (IFN) receptor (IFNAR) is critical in host resistance against ZIKV (9-11), and that persistent replication of the virus within the testes of infected IFNAR-deficient male mice (9). Subcutaneous ZIKV infection of Ifnar-/- dams mated with WT sires results in intrauterine growth restriction (IUGR) (12). However, virtually nothing is known about either the pathogenesis of sexual Zika virus transmission, or the defense mechanisms that prevent sexual transmission of ZIKV in pregnant women or the fetus. To this end, we developed the first vaginal ZIKV transmission model in mice. Remarkably, vaginal infection of pregnant mice results in IUGR and infection within the cerebellum and cortex of the fetal brain. Moreover, by using mice that lack various innate sensor and signaling pathways, we unveiled the role of each pathway in controlling ZIKV replication and spread from the vaginal mucosa to the fetus. Using this unique approach, we will find urgently needed answers to the following key questions - 1) which innate signaling pathways block ZIKV in the virgin vs. pregnant female mice; and 2) what innate antiviral pathways are important to restrict ZIKV infection within the fetus?

项目摘要 Zika病毒（Zikv）以通过伊蚊的传播而闻名，但最近的证据 突出显示与感染伴侣的性接触是另一种重要的传播途径。有 多次确认和怀疑的人类性传播案件，所有这些涉及传播 从感染的男人到女性伴侣通过阴道性交（1-7）。 ZIKV已在精液中检测到 被感染的男人（4、6、8）。这些研究共同表明，从感染男性到 未感染的女性发生在人类中。一个重要的临床问题是ZIKV是否可以性传播 在孕妇中，这种感染的后果可能是怀孕的结果。这 CDC敦促患有ZIKV疾病的男性在症状发作后至少等待6个月进行尝试（5）。 但是，怀孕期间ZIKV的性传播的后果尚不清楚。最近三个 使用ZIKV小鼠模型的研究表明，I型干扰素（IFN）受体（IFNAR）在 宿主抵抗ZIKV（9-11），并在感染的睾丸中持续复制病毒 IFNAR缺陷型雄性小鼠（9）。与WT Sires交配的IFNAR - / - 大坝的皮下ZIKV感染导致 宫内生长限制（IUGR）（12）。但是，对发病机理几乎一无所知 性寨卡病毒传播或防止ZIKV性传播的防御机制 孕妇或胎儿。为此，我们开发了第一个阴道ZIKV传播模型 老鼠。值得注意的是，怀孕小鼠的阴道感染导致小脑内的IUGR和感染 胎儿的皮质。此外，通过使用缺乏固有传感器和信号通路的小鼠，我们 揭示了每种途径在控制ZIKV复制中的作用，并从阴道粘膜传播到 胎儿。使用这种独特的方法，我们将急需解决以下关键问题的答案-1） 天生的信号通路阻止了处女与怀孕的雌性小鼠的ZIKV； 2）什么先天抗病毒 途径对于限制胎儿内的ZIKV感染很重要？