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

IL-1β 调节 Zika 介导的不良围产期结局

• 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
• 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

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 怀孕女性的寨卡病毒（ZIKV）感染导致后代和长期感染 发展出生缺陷。使用我们开发的免疫功能的鼠标模型（发表在 自然通讯），我们已经表明，非洲，美国或亚洲的宫内感染 早期但不晚的ZIKV菌株，妊娠会引起斑点和胎儿的感染，胎盘 后代的炎症，新生儿皮质稀疏和短期神经系统防御。最近，我们有 证明ZIKV感染的大坝中占地IL-1β浓度升高，我们可以逆转 ZIKV相关的短期神经性后遗症在后代中通过阻止IL-1受体信号传导 感染。我们假设宫内ZIKV感染后的斑点注射会导致围产期 神经损伤，可以通过靶向MATER IL-1β信号来逆转。而大多数zikv 干预措施集中于抗病毒药和疫苗以限制围产期ZIKV感染，迄今为止没有研究 认为孕产妇和斑点炎症的作用是介导的长期不良的机制 ZIKV感染后的围产期结局。具体目标1将评估介导升高IL-的机制 ZIKV感染后，在不同胎龄的plapeta中的1β信号传导，长期下游 位置免疫病理学和位置IL-1β信号的影响，以及这些影响是否是性别 具体的。特别是，AIM 1将确定局部炎症体激活，IL-1β释放或 IL-1受体的参与导致围产期不良结果。特定目标2将检查 孕产妇在围产期脑损伤的发病机理中与胎儿IL-1β信号的重要性 ZIKV感染后。使用IL-1β信号传导不足和野生型小鼠菌株的胚胎转移，AIM 2 将评估母体起源的IL-1β活性对于性别特异性胎儿脑损伤至关重要。我们的小说 使用我们开发的ZIKV模型的转化研究建议将对 围产作用，因为它将更好地理解位置感染在 怀孕期间由感染或其他炎症状态引起的胎儿先天性疾病的发病机理。