IL-1β regulation of Zika-mediated adverse perinatal outcomes

IL-1β 调节 Zika 介导的不良围产期结局

基本信息

批准号：
10438667
负责人：
IRINA BURD
金额：
$ 13.81万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-21 至 2022-10-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10438667
关键词：
Address Adverse effects Affect African American Antiviral Agents Asian Birth Brain Communication Congenital Abnormality Data Development Disease Dose Embryo Transfer Family Female Fetal Development Fetus Flaviviridae Genetic Gestational Age Immunocompetent Immunomodulators Infection Inflammasome Inflammation Inflammatory Interleukin-1 Receptors Interleukin-1 beta Intervention Kineret Kinetics Lead Mediating Microcephaly Modeling Mouse Strains Nature Neonatal Nervous System Trauma Neurologic Deficit Outcome Pathogenesis Perinatal Perinatal Brain Injury Pharmaceutical Preparations Pharmacology Placenta Pregnancy Problem behavior Production Publishing RNA Viruses Receptor Signaling Recombinants Regulation Research Proposals Role Sex Differences Signal Transduction Testing Therapeutic Intervention Thinness Translational Research Vaccines Viral Load result Viral Pathogenesis Wild Type Mouse ZIKA ZIKV infection Zika Virus adverse outcome brain abnormalities congenital infection early pregnancy experimental study fetal fetal brain injury fetal infection immunopathology improved in utero intrauterine infection intrauterine inflammation long-term sequelae mouse model neurobehavioral neurotoxicity novel offspring perinatal medicine perinatal outcomes placental infection pregnant prenatal exposure receptor receptor binding response sex therapeutically effective tool

项目摘要

SUMMARY Zika virus (ZIKV) infection of pregnant females results in congenital infection of offspring and long-term developmental birth defects. Using an immunocompetent mouse model that we developed (published in Nature Communications), we have shown that intrauterine infection with either African, American, or Asian strains of ZIKV during early, but not late, pregnancy causes infection of the placenta and fetuses, placental inflammation, neonatal cortical thinning, and short-term neurologic deficits in offspring. More recently, we have demonstrated that placental IL-1β concentrations are elevated in ZIKV-infected dams, and we can reverse the ZIKV-associated short-term neurobehavioral sequelae in offspring by blocking IL-1 receptor signaling during the infection. We hypothesize that placental inflammation following intrauterine ZIKV infection causes perinatal neurological injury, which can then be reversed by targeting maternal IL-1β signaling. While most ZIKV interventions focus on antivirals and vaccines to limit perinatal ZIKV infection, to date no studies have considered the role of maternal and placental inflammation as a mechanism mediating long-term adverse perinatal outcomes following ZIKV infection. Specific Aim 1 will assess the mechanisms mediating elevated IL- 1β signaling in the placenta at different gestational ages following ZIKV infection, the long-term downstream effects of the placental immunopathology and placental IL-1β signaling, and whether these effects are sex- specific. In particular, Aim 1 will determine how placental inflammasome activation, IL-1β release, or engagement of the IL-1 receptor lead to adverse perinatal outcomes. Specific Aim 2 will examine the importance of maternal as opposed to fetal IL-1β signaling in the pathogenesis of perinatal brain injury following ZIKV infection. Using embryo transfer of IL-1β signaling deficient and wild type mouse strains, Aim 2 will assess whether IL-1β activity of maternal origin is critical for sex-specific fetal brain injury. Our novel translational research proposal, utilizing a ZIKV model that we developed, will have a significant impact on perinatal medicine as it will lead to a better understanding of the role of placental inflammation in the pathogenesis of fetal congenital diseases caused by infection or other inflammatory states during pregnancy.

概括怀孕女性感染寨卡病毒（ZIKV）会导致后代先天性感染并长期感染使用我们开发的免疫活性小鼠模型（发表于《自然通讯》），我们已经证明，非洲、美洲或亚洲人的宫内感染寨卡病毒株在妊娠早期（而非晚期）会导致胎盘和胎儿感染，胎盘最近，我们发现了后代的炎症、新生儿皮质变薄和短期神经功能缺陷。感染 ZIKV 的母鼠的胎盘 IL-1β 浓度升高，我们可以逆转通过阻断 IL-1 受体信号传导，在后代中产生与 ZIKV 相关的短期神经行为后遗症我们追查宫内 ZIKV 感染后的胎盘炎症会导致围产期。神经损伤，然后可以通过针对母体 IL-1β 信号传导来逆转，而大多数 ZIKV 则可以逆转这种损伤。干预措施的重点是抗病毒药物和疫苗，以限制围产期 ZIKV 感染，迄今为止尚无研究表明认为母体和胎盘炎症作为介导长期不良反应的机制的作用 ZIKV 感染后的围产期结局具体目标 1 将评估介导 IL-升高的机制。 ZIKV 感染后不同胎龄胎盘中的 1β 信号传导是长期下游胎盘免疫病理学和胎盘 IL-1β 信号传导的影响，以及这些影响是否与性别相关特别是，目标 1 将确定胎盘炎症小体如何激活、IL-1β 释放或如何发生。 IL-1 受体的参与会导致不良的围产期结局。母体对胎儿 IL-1β 信号的重要性在围产期脑损伤的发病机制中相反 ZIKV 感染后使用 IL-1β 信号传导缺陷和野生型小鼠品系的胚胎移植，目标 2 将评估母体来源的 IL-1β 活性是否对性别特异性胎儿脑损伤至关重要。利用我们开发的 ZIKV 模型的转化研究提案将对围产期医学，因为它将有助于更好地了解胎盘炎症在胎儿发育过程中的作用妊娠期感染或其他炎症状态引起的胎儿先天性疾病的发病机制。