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.

总结 孕妇感染寨卡病毒（ZIKV）会导致后代先天性感染， 发育性出生缺陷。使用我们开发的免疫活性小鼠模型（发表于 自然通讯），我们已经表明，无论是非洲人，美洲人，还是亚洲人， 在妊娠早期而非晚期，ZIKV株引起胎盘和胎儿感染，胎盘感染 炎症、新生儿皮质变薄和后代短期神经功能缺损。最近，我们有 研究表明，胎盘IL-1β浓度在ZIKV感染的母鼠中升高，我们可以逆转这种情况。 ZIKV相关的短期神经行为后遗症在后代中通过阻断IL-1受体信号传导， 感染我们假设子宫内ZIKV感染后的胎盘炎症导致围产期 神经损伤，然后可以通过靶向母体IL-1β信号转导来逆转。虽然大多数ZIKV 干预措施集中在抗病毒药物和疫苗，以限制围产期ZIKV感染，迄今为止，没有研究 认为母体和胎盘炎症的作用是介导长期不良反应的机制， ZIKV感染后的围产期结局。特异性目的1将评估介导IL-2升高的机制。 ZIKV感染后不同胎龄胎盘中的1β信号传导， 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有关。 特定.特别是，Aim 1将确定胎盘炎性小体激活、IL-1β释放或 IL-1受体的参与导致不良的围产期结果。具体目标2将审查 母体与胎儿IL-1β信号在围产期脑损伤发病机制中的重要性 ZIKV感染后。利用IL-1β信号转导缺陷小鼠和野生型小鼠的胚胎移植， 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。我们的新型 利用我们开发的ZIKV模型的转化研究提案将对 围产期医学，因为它将导致更好地了解胎盘炎症的作用， 妊娠期间感染或其他炎症状态引起的胎儿先天性疾病的发病机制。