Vertical Transmission of Zika Virus in Pregnant Olive Baboons Following Vaginal Infection

项目摘要 妊娠期寨卡病毒（ZIKV）感染与一系列胎儿异常有关，包括小头畸形和 其他CNS病变。ZIKV的男性对女性的性传播是有据可查的。ZIKV转移到精液 并且比血液更持久。在阴道和宫颈粘液中ZIKV的长期检测已经被证实是有效的。 在人类身上发现的。未怀孕猕猴的阴道ZIKV感染导致雌性的长期感染 生殖道和全身感染。因此，阴道似乎是ZIKV的有利环境。 繁殖和感染。橄榄狒狒（Papio anubis）在遗传、体型、 生殖生理学、胎盘形成和免疫系统使这种灵长类动物成为一种优秀的翻译 用于研究妊娠期间ZIKV感染的模型。我们的团队有用黄病毒感染狒狒的经验。我们 初步数据显示，在怀孕期间皮下（sc）ZIKV接种可导致垂直ZIKV 转移到胎儿中枢神经系统。我们假设，在怀孕妇女中阴道接种ZIKV感染的精液， 狒狒将导致1）ZIKV在CV道中持续时间延长并传播至局部泌尿生殖道 包括靶向树突状细胞、巨噬细胞和淋巴细胞在内的抗肿瘤药物，增强ZIKV向 子宫，2）CV粘膜免疫和炎症反应的激活，包括免疫细胞迁移 3）增强的胎盘ZIKV感染导致增强的胎盘ZIKV（单核细胞、嗜中性粒细胞、T细胞）进入CV组织， ZIKV通过泌尿生殖道感染子宫和/或ZIKV通过宫颈管Ascension至子宫颈， 宫内隔室和4）ZIKV的垂直传播增强，胎儿CZS更严重 病理学和/或妊娠丢失。我们将确定妊娠狒狒阴道接种的效果， ZIKV感染的精液在早期（妊娠50天，dG）和中期（90 dG;）妊娠期间的目标1）持续性 ZIKV在CV道中传播并扩散到局部泌尿生殖淋巴系统，目的2）CV先天性 和适应性免疫应答（免疫细胞募集到CV组织、CV炎症、粘膜伊加 3）ZIKV感染和子宫及垂直传播胎盘和胎儿的病理学。我们 将感染妊娠早期（妊娠50天[dG]）和中期（90 dG;足月~181 dG）狒狒，代表 灵长类动物CNS发育的独特时期，具有潜在的不同CNS结局。ZIKV感染早期 妊娠中期与人类中最严重的胎儿CNS结果有关。妊娠将在近期终止 (170在一个组群中在组织收集后28天，在第二个组群中在母体ZIKV病毒血症发作后28天， 允许ZIKV的急性（细胞/组织靶向）和慢性母胎病理学作用的队列， 接受检查。我们将比较阴道感染的结果，我们正在进行的项目使用sc途径， 接种以及年龄匹配的对照妊娠。

PROJECT SUMMARY Zika virus (ZIKV) infection in pregnancy is linked to a spectrum of fetal anomalies including microcephaly and other CNS lesions. Male-to-female sexual transmission of ZIKV is well documented. ZIKV transfers to semen and persists much longer vs. blood. Prolonged detection of ZIKV in the vagina and cervical mucus has been noted in humans. Vaginal ZIKV infection of non-pregnant macaques leads to prolonged infection of the female reproductive tract and systemic infection. Thus, the vagina appears to be a favorable environment for ZIKV propagation and infection. The olive baboon's (Papio anubis) similarity to humans in terms of genetics, size, reproductive physiology, placentation and immune repertoire makes this primate an excellent translational model for studying ZIKV infection during pregnancy. Our team has flavivirus experience with the baboon. Our preliminary data show that subcutaneous (sc) ZIKV inoculation during pregnancy can lead to vertical ZIKV transfer to the fetal CNS. We hypothesize that vaginal inoculation of ZIKV infected semen in pregnant baboons will result in 1) prolonged ZIKV persistence in the CV tract and dissemination to the local urogenital lymphatics, including targeting of dendritic cells, macrophages and lymphocytes, enhancing ZIKV transfer to the uterus, 2) activation of a CV mucosal immune and inflammatory response including immune cell migration (monocyte, neutrophil, T cell) into CV tissue, 3) enhanced placental ZIKV infection resulting from enhanced ZIKV infection of the uterus via urogenital lymphatics and/or ZIKV ascension through the cervical canal to the intrauterine compartment and 4) enhanced vertical transmission of ZIKV with a more severe fetal CZS pathology and/or pregnancy loss. We will determine the effect of vaginal inoculation of pregnant baboons with ZIKV-infected semen during early- (50 days gestation, dG), and mid- (90 dG;) gestation on Aim 1) persistence and propagation of ZIKV in the CV tract and spread to the local urogenital lymphatic system, Aim 2) CV innate and adaptive immune responses (immune cell recruitment into CV tissue, CV inflammation, mucosal IgA response) and Aim 3) ZIKV infection and pathology of uterus and vertical transmission placenta and fetus. We will infect early- (50 days gestation [dG]), and mid- (90 dG; term ~181 dG) gestation baboons representing unique periods of primate CNS development with potentially different CNS outcomes. ZIKV infection in early to mid-gestation is linked to most severe fetal CNS outcome in humans. Pregnancies will be terminated near term (170+/1 dG) for tissue collection in one cohort and at 28 days post-onset of maternal ZIKV viremia in a second cohort allowing both acute (cellular/tissue targeting) and chronic maternal-fetal pathological effects of ZIKV to be examined. We will compare outcomes from vaginal infection to our ongoing project using sc route of inoculation as well as to age-matched control pregnancies.