Vertical Transmission of Zika Virus in Pregnant Olive Baboons FollowingVaginal Infection

项目总结 孕期寨卡病毒(ZIKV)感染与一系列胎儿畸形有关，包括小头畸形和 其他中枢神经系统病变。寨卡病毒在男性和女性之间的性传播已经有了很好的记录。ZIKV转移到精液 与血液相比，持续时间要长得多。在阴道和宫颈粘液中长期检测到寨卡病毒 在人类身上发现的。非孕猕猴经阴道感染寨卡病毒可导致雌性猕猴长期感染 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)在遗传学、体型、 生殖生理、胎盘和免疫系统使这种灵长类成为一种优秀的翻译 研究孕期寨卡病毒感染的模型。我们的团队有与狒狒接触过黄病毒的经验。我们的 初步数据显示，孕期皮下接种ZIKV可导致垂直ZIKV 转移到胎儿的中枢神经系统。我们推测孕期经阴道接种寨卡病毒感染的精液 狒狒将导致1)ZIKV在CV道中持续时间延长，并传播到当地的泌尿生殖系统 淋巴管，包括靶向树突状细胞、巨噬细胞和淋巴细胞，促进ZIKV转移到 子宫，2)激活CV粘膜免疫和炎症反应，包括免疫细胞迁移 (单核细胞、中性粒细胞、T细胞)进入CV组织，3)增强的胎盘ZIKV感染 ZIKV通过泌尿生殖道淋巴管感染子宫和/或ZIKV通过宫颈上升至 宫腔内和4)ZIKV垂直传播增强并伴有更严重的胎儿CZS 病理和/或妊娠丢失。我们将确定经阴道接种怀孕狒狒的效果。 ZIKV感染的精液在妊娠早期(妊娠50天)和中期(妊娠90天)持续1) 和ZIKV在CV道中的繁殖，并扩散到当地的泌尿生殖系统，目的是先天性CV 和获得性免疫反应(免疫细胞重新聚集到CV组织、CV炎症、粘膜IgA 回答)和目的3)ZIKV感染与子宫、垂直传播胎盘和胎儿的病理。我们 将感染妊娠早期(50天妊娠[DG])和中期(90 DG；足月~181 DG)的狒狒，代表 灵长类中枢神经系统发育的独特时期具有潜在不同的中枢神经系统结果。寨卡病毒感染在早期到 妊娠中期与人类最严重的胎儿中枢神经系统结局有关。怀孕将在近期终止。 (170+/1 DG)，用于在一个队列中收集组织，并在母亲ZIKV病毒血症起病后28天第二次 允许ZIKV急性(细胞/组织靶向)和慢性母婴病理效应的队列 接受检查。我们将使用sc途径将阴道感染的结果与我们正在进行的项目进行比较。 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.