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

阴道感染后怀孕橄榄狒狒中寨卡病毒的垂直传播

基本信息

批准号：
9752914
负责人：
DEAN MYERS
金额：
$ 21.75万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-26 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9752914
关键词：
Acute Aedes Age Americas Animal Model Blood Brain Cell Culture Techniques Cells Centers for Disease Control and Prevention (U.S.)Cerebral cortex Cervical Cervix Mucus Chronic Congenital Abnormality Coupled Culicidae Culture Media Data Dendritic Cells Deposition Detection Environment Epidemic Female Fetal Development Fetal Growth Retardation Fetus Flavivirus Flavivirus Infections Focal Infection Genetic Genitourinary system Human Immune Immunoglobulin A Immunoglobulin G In Vitro Infant Infection Inflammation Inflammatory Response Interferon Type I International Lead Lesion Link Lymphatic Lymphatic System Lymphocyte Macaca Microcephaly Modeling Mucosal Immune Responses Mucous Membrane Mus Neuraxis Outcome Papio Papio anubis Pathologic Pathology Placenta Placentation Pregnancy Pregnancy Outcome Pregnancy loss Pregnant Women Primates Reporting Reproductive Physiology Resolution Role Route Seminal fluid Sexual Transmission Sexual transmission of Zika Signal Transduction Study models Systemic infection T-Lymphocyte Tissue Banks Tissues United States National Institutes of Health Urine Uterus Vagina Vaginal delivery procedure Vero Cells Vertical Disease Transmission Villous Viral Viremia Virus Wild Type Mouse World Health Organization ZIKV disease ZIKV infection Zika Virus adaptive immune response cell motility cervicovaginal chemokine cohort congenital zika syndrome cytokine experience fetal fetal infection infection risk innovation lymph nodes macrophage male monocyte mouse model nervous system development neurodevelopment neutrophil nonhuman primate pregnant public health emergency recruit reproductive tract response subcutaneous tissue tropism translational model transmission process vaginal infection

项目摘要

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.

项目概要妊娠期寨卡病毒 (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。寨卡病毒从男性到女性的性传播已有充分记录。 ZIKV 转移至精液与血液相比，其持续时间更长。阴道和宫颈粘液中长期检测到 ZIKV 在人类中注意到。未怀孕猕猴的阴道 ZIKV 感染导致雌性猕猴感染时间延长生殖道和全身感染。因此，阴道似乎是 ZIKV 的有利环境传播和感染。橄榄狒狒（Papio anubis）在遗传、体型、生殖生理学、胎盘和免疫系统使这种灵长类动物成为优秀的转化动物研究妊娠期间 ZIKV 感染的模型。我们的团队拥有狒狒黄病毒治疗经验。我们的初步数据显示，怀孕期间皮下（sc）ZIKV 接种可导致垂直 ZIKV 转移至胎儿中枢神经系统。我们假设怀孕期间阴道接种了 ZIKV 感染的精液狒狒将导致 1) ZIKV 在CV道中持续存在并传播到局部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，增强 ZIKV 转移至子宫，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 通过泌尿生殖淋巴管感染子宫和/或 ZIKV 通过宫颈管上升至子宫宫内间隔和 4) 增强 ZIKV 的垂直传播并导致更严重的胎儿 CZS 病理和/或流产。我们将确定怀孕狒狒阴道接种的效果 ZIKV 感染的精液在妊娠早期（50 天，dG）和中期（90 dG；）目标 1）持续存在 ZIKV 在 CV 道中传播并扩散到局部泌尿生殖淋巴系统，目标 2) CV 先天性和适应性免疫反应（免疫细胞募集到 CV 组织、CV 炎症、粘膜 IgA 反应）和目标 3）ZIKV 感染和子宫病理以及胎盘和胎儿垂直传播。我们将感染早期（50 天妊娠 [dG]）和中期（90 dG；足月 ~181 dG）妊娠狒狒灵长类中枢神经系统发育的独特时期可能具有不同的中枢神经系统结果。 ZIKV 感染早期妊娠中期与人类最严重的胎儿中枢神经系统结局有关。近期将终止妊娠 (170+/1 dG) 在一个队列中进行组织收集，在第二个队列中在母体 ZIKV 病毒血症发作后 28 天进行组织收集队列允许 ZIKV 的急性（细胞/组织靶向）和慢性母胎病理效应被检查。我们将使用皮下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。